Kinase inhibitors: the road ahead (original) (raw)

• U.S. Food & Drug Administration. New drugs at FDA: CDER's new molecular entities and new therapeutic biological products. FDA https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/default.htm (2017).
• Cohen, P. & Alessi, D. R. Kinase drug discovery — what's next in the field? ACS Chem. Biol. 8, 96–104 (2013).
  Article CAS PubMed Google Scholar
• Ficarro, S. B. et al. Phosphoproteome analysis by mass spectrometry and its application to Saccharomyces cerevisiae. Nat. Biotechnol. 20, 301–305 (2002).
  CAS PubMed Google Scholar
• Cohen, P. The regulation of protein function by multisite phosphorylation — a 25 year update. Trends Biochem. Sci. 25, 596–601 (2000).
  CAS PubMed Google Scholar
• Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).
  CAS PubMed Google Scholar
• Muller, S., Chaikuad, A., Gray, N. S. & Knapp, S. The ins and outs of selective kinase inhibitor development. Nat. Chem. Biol. 11, 818–821 (2015).
  CAS PubMed Google Scholar
• Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 36, 462–469 (2003).
  CAS PubMed Google Scholar
• National Institutes of Health Office of Strategic Coordination - The Common Fund. Understudied proteins. NIH https://commonfund.nih.gov/idg/understudiedproteins (2017).
• Fedorov, O., Muller, S. & Knapp, S. The (un)targeted cancer kinome. Nat. Chem. Biol. 6, 166–169 (2010).
  CAS PubMed Google Scholar
• Botta, M. New frontiers in kinases: special issue. ACS Med. Chem. Lett. 5, 270 (2014).
  CAS PubMed PubMed Central Google Scholar
• Zhao, Q. et al. Broad-spectrum kinase profiling in live cells with lysine-targeted sulfonyl fluoride probes. J. Am. Chem. Soc. 139, 680–685 (2017). This paper describes an in cell competition assay to discern kinase inhibitor selectivity in a physiological context.
  CAS PubMed PubMed Central Google Scholar
• Savitski, M. M. et al. Tracking cancer drugs in living cells by thermal profiling of the proteome. Science 346, 1255784 (2014). This paper describes a proteome-wide profiling technique based on the CETSA assay.
  Article PubMed Google Scholar
• Aldeghi, M., Heifetz, A., Bodkin, M. J., Knapp, S. & Biggin, P. C. Predictions of ligand selectivity from absolute binding free energy calculations. J. Am. Chem. Soc. 139, 946–957 (2017). This article describes an unusually accurate computational method to determine inhibitor selectivity.
  CAS PubMed Google Scholar
• Dale, T. et al. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat. Chem. Biol. 11, 973–980 (2015).
  CAS PubMed PubMed Central Google Scholar
• Alexander, P. B. & Wang, X. F. Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies. Front. Med. 9, 134–138 (2015).
  PubMed PubMed Central Google Scholar
• Villicana, C., Cruz, G. & Zurita, M. The basal transcription machinery as a target for cancer therapy. Cancer Cell. Int. 14, 18 (2014).
  PubMed PubMed Central Google Scholar
• Bradner, J. E., Hnisz, D. & Young, R. A. Transcriptional addiction in cancer. Cell 168, 629–643 (2017).
  CAS PubMed PubMed Central Google Scholar
• Nie, Z. et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68–79 (2012).
  CAS PubMed PubMed Central Google Scholar
• Kwiatkowski, N. et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511, 616–620 (2014). This paper demonstrates effective targeting of transcriptional vulnerabilities in cancer via a covalent CDK7 kinase inhibitor.
  CAS PubMed PubMed Central Google Scholar
• Christensen, C. L. et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26, 909–922 (2014).
  CAS PubMed PubMed Central Google Scholar
• Chipumuro, E. et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159, 1126–1139 (2014).
  CAS PubMed PubMed Central Google Scholar
• Bywater, M. J., Pearson, R. B., McArthur, G. A. & Hannan, R. D. Dysregulation of the basal RNA polymerase transcription apparatus in cancer. Nat. Rev. Cancer 13, 299–314 (2013).
  CAS PubMed Google Scholar
• Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
  CAS PubMed Google Scholar
• Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
  CAS PubMed Google Scholar
• Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
  CAS PubMed Google Scholar
• Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).
  CAS PubMed PubMed Central Google Scholar
• Hann, S. R. & Eisenman, R. N. Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells. Mol. Cell. Biol. 4, 2486–2497 (1984).
  CAS PubMed PubMed Central Google Scholar
• Herrick, D. J. & Ross, J. The half-life of c-myc mRNA in growing and serum-stimulated cells: influence of the coding and 3' untranslated regions and role of ribosome translocation. Mol. Cell. Biol. 14, 2119–2128 (1994).
  CAS PubMed PubMed Central Google Scholar
• Posternak, V. & Cole, M. D. Strategically targeting MYC in cancer. F1000Res. 5, 408 (2016).
  Google Scholar
• Gonda, T. J. & Ramsay, R. G. Directly targeting transcriptional dysregulation in cancer. Nat. Rev. Cancer 15, 686–694 (2015).
  CAS PubMed Google Scholar
• Di Vona, C. et al. Chromatin-wide profiling of DYRK1A reveals a role as a gene-specific RNA polymerase II CTD kinase. Mol. Cell 57, 506–520 (2015).
  CAS PubMed Google Scholar
• Ionescu, A. et al. DYRK1A kinase inhibitors with emphasis on cancer. Mini Rev. Med. Chem. 12, 1315–1329 (2012).
  CAS PubMed Google Scholar
• Zhou, Y., Shen, J. K., Hornicek, F. J., Kan, Q. & Duan, Z. The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer. Oncotarget 7, 40846–40859 (2016).
  PubMed PubMed Central Google Scholar
• Schachter, M. M. & Fisher, R. P. The CDK-activating kinase Cdk7: taking yes for an answer. Cell Cycle 12, 3239–3240 (2013).
  CAS PubMed PubMed Central Google Scholar
• Guo, J. & Price, D. H. RNA polymerase II transcription elongation control. Chem. Rev. 113, 8583–8603 (2013).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03269669 (2018).
• Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).
  PubMed PubMed Central Google Scholar
• Pelish, H. E. et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526, 273–276 (2015). This paper describes a highly selective natural product inhibitor of CDK8, cortistatin A, which downregulates SE-associated genes in AML. This study also introduces the concept that cancer cells are highly sensitive to SE-controlled gene dosage; both upregulation and downregulation of these genes is toxic.
  CAS PubMed PubMed Central Google Scholar
• Clarke, P. et al. Discovery of preclinical development candidate inhibitors of the mediator complex-associated kinases CDK8 and CDK19 and evaluation of their therapeutic potential [abstract]. Cancer Res. 76 (Suppl.), 3025 (2016).
  Google Scholar
• Bahr, B. L. et al. Combination strategies to target super enhancer transcriptional activity by CDK9 and BRD4 inhibition in acute myeloid leukemia [abstract]. Cancer Res. 75 (Suppl.), 2698 (2015).
  Google Scholar
• Sonawane, Y. A. et al. Cyclin dependent kinase 9 inhibitors for cancer therapy. J. Med. Chem. 59, 8667–8684 (2016).
  CAS PubMed PubMed Central Google Scholar
• Yin, T. et al. B.; de Dios, A. ; Du, J., A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol. Cancer Ther. 13, 1442–1456 (2014).
  CAS PubMed Google Scholar
• Morales, F. & Giordano, A. Overview of CDK9 as a target in cancer research. Cell Cycle 15, 519–527 (2016).
  CAS PubMed PubMed Central Google Scholar
• Lu, H. et al. Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism. eLife 4, e06535 (2015).
  PubMed PubMed Central Google Scholar
• Barsanti, P. A. et al. Pyridine and pyrazine derivatives as protein kinase modulators. US Patent WO2011012661 A1 (2010).
• Liang, K. et al. Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing. Mol. Cell. Biol. 35, 928–938 (2015).
  CAS PubMed PubMed Central Google Scholar
• Zhang, T. et al. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat. Chem. Biol. 12, 876–884 (2016). This paper describes an inhibitor that induces a loop rearrangement, enabling covalent inhibition of a distal cysteine by an ATP-competitive inhibitor.
  CAS PubMed PubMed Central Google Scholar
• Hamman, K. et al. Targeting the transcriptional kinases CDK12 and CDK13 in breast and ovarian cancer [abstract]. FASEB J. 31 (Suppl. 1), 938.9 (2017).
  Google Scholar
• Johnson, S. F. et al. CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep. 17, 2367–2381 (2016).
  CAS PubMed PubMed Central Google Scholar
• Bao, Z. et al. Effectiveness and safety of poly (ADP-ribose) polymerase inhibitors in cancer therapy: a systematic review and meta-analysis. Oncotarget 7, 7629–7639 (2016).
  PubMed Google Scholar
• Vinay, D. S. et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 35 (Suppl.), S185–S198 (2015).
  PubMed Google Scholar
• Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
  CAS PubMed PubMed Central Google Scholar
• Sukari, A., Nagasaka, M., Al-Hadidi, A. & Lum, L. G. Cancer Immunology and immunotherapy. Anticancer Res. 36, 5593–5606 (2016).
  CAS PubMed Google Scholar
• Lemke, G. & Rothlin, C. V. Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8, 327–336 (2008).
  CAS PubMed PubMed Central Google Scholar
• Seitz, H. M., Camenisch, T. D., Lemke, G., Earp, H. S. & Matsushima, G. K. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J. Immunol. 178, 5635–5642 (2007).
  CAS PubMed Google Scholar
• Caraux, A. et al. Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases. Nat. Immunol. 7, 747–754 (2006).
  CAS PubMed Google Scholar
• Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44, 852–860 (2012).
  CAS PubMed PubMed Central Google Scholar
• Postel-Vinay, S. & Ashworth, A. AXL and acquired resistance to EGFR inhibitors. Nat. Genet. 44, 835–836 (2012).
  CAS PubMed Google Scholar
• [No authors listed.] Clinical trials. BerGenBio http://www.bergenbio.com/pipeline/ongoing-clinical-trials/ (2017).
• Myers, S. H., Brunton, V. G. & Unciti-Broceta, A. AXL inhibitors in cancer: a medicinal chemistry perspective. J. Med. Chem. 59, 3593–3608 (2016).
  CAS PubMed Google Scholar
• Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014). This paper validates TAM kinases as therapeutic targets in cancer, demonstrating that their pharmacological inhibition enhances anti-metastatic NK cell activity.
  CAS PubMed PubMed Central Google Scholar
• Putz, E. M. et al. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 4, 437–444 (2013).
  CAS PubMed PubMed Central Google Scholar
• Johannessen, L. et al. Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells. Nature Chem. Biol. 13, 1102–1108 (2017).
  CAS Google Scholar
• Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).
  CAS PubMed PubMed Central Google Scholar
• Quail, D. F. et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 (2016). References 64 and 65 describe CSF-1R, an anti-inflammatory target in glioma, and demonstrate that tumour microenvironment-mediated resistance can be overcome by combination with IGF-1R or PI3K inhibitors.
  PubMed PubMed Central Google Scholar
• Rommel, C. Taking PI3Kdelta and PI3Kgamma one step ahead: dual active PI3Kdelta/gamma inhibitors for the treatment of immune-mediated inflammatory diseases. Curr. Top. Microbiol. Immunol. 346, 279–299 (2010).
  CAS PubMed Google Scholar
• Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).
  CAS PubMed PubMed Central Google Scholar
• Ali, K. et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407–411 (2014).
  CAS PubMed PubMed Central Google Scholar
• Ferguson, F. M. et al. Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-delta/gamma Inhibitors. ACS Med. Chem. Lett. 7, 908–912 (2016).
  CAS PubMed PubMed Central Google Scholar
• O'Brien, S. et al. Duvelisib (IPI-145), a PI3K-δ, γ inhibitor, is clinically active in patients with relapsed/refractory chronic lymphocytic leukemia. Blood 124, 3334–3334 (2014).
  Google Scholar
• Horwitz, S. M. et al. Activity of the PI3K-delta, gamma inhibitor duvelisib in a phase I trial and preclinical models of T-cell lymphoma. Blood https://doi.org/10.1182/blood-2017-08-802470 (2017).
  PubMed Google Scholar
• Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
  CAS PubMed PubMed Central Google Scholar
• Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).
  CAS PubMed Google Scholar
• Gong, Y. & Pao, W. EGFR mutant lung cancer. Curr. Top. Microbiol. Immunol. 355, 59–81 (2012).
  CAS PubMed Google Scholar
• Barouch-Bentov, R. & Sauer, K. Mechanisms of drug-resistance in kinases. Expert Opin. Investig. Drugs 20, 153–208 (2011).
  CAS PubMed PubMed Central Google Scholar
• Vanneman, M. & Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237–251 (2012).
  CAS PubMed PubMed Central Google Scholar
• Gainor, J. F. et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin. Cancer Res. 22, 4585–4593 (2016).
  CAS PubMed PubMed Central Google Scholar
• Shin, D. S. & Ribas, A. The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr. Opin. Immunol. 33, 23–35 (2015).
  CAS PubMed Google Scholar
• Mahoney, K. M., Rennert, P. D. & Freeman, G. J. Combination cancer immunotherapy and new immuno-modulatory targets. Nat. Rev. Drug Discov. 14, 561–584 (2015).
  CAS PubMed Google Scholar
• Tchekmedyian, N. et al. Propelling immunotherapy combinations into the clinic. Oncology 29, 990–1002 (2015).
  PubMed Google Scholar
• Kaneda, M. M. et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016).
  CAS PubMed PubMed Central Google Scholar
• Schmid, M. C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715–727 (2011).
  CAS PubMed PubMed Central Google Scholar
• Diaz-Montero, C. M., Finke, J. & Montero, A. J. Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications. Semin. Oncol. 41, 174–184 (2014).
  CAS PubMed PubMed Central Google Scholar
• Gebhardt, C. et al. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin. Cancer Res. 21, 5453–5459 (2015).
  CAS PubMed Google Scholar
• De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature 539, 443–447 (2016).
  CAS PubMed PubMed Central Google Scholar
• Evans, C. A. et al. Discovery of a selective phosphoinositide-3-kinase (PI3K)-gamma inhibitor (IPI-549) as an immuno-oncology clinical candidate. ACS Med. Chem. Lett. 7, 862–867 (2016).
  CAS PubMed PubMed Central Google Scholar
• Ebert, P. J. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).
  CAS PubMed Google Scholar
• Serrels, A. et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015).
  CAS PubMed PubMed Central Google Scholar
• Stokes, J. B. et al. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol. Cancer Ther. 10, 2135–2145 (2011).
  CAS PubMed PubMed Central Google Scholar
• Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).
  CAS PubMed PubMed Central Google Scholar
• Huang, S. H., Li, Y., Zhang, J., Rong, J. & Ye, S. Epidermal growth factor receptor-containing exosomes induce tumor-specific regulatory T cells. Cancer Invest. 31, 330–335 (2013).
  CAS PubMed Google Scholar
• Ahn, M. J., Sun, J. M., Lee, S. H., Ahn, J. S. & Park, K. EGFR TKI combination with immunotherapy in non-small cell lung cancer. Expert Opin. Drug Safety 16, 465–469 (2017).
  CAS Google Scholar
• Akbay, E. A. et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 3, 1355–1363 (2013). This paper describes the immunosuppressive functions of oncogenic EGFR and demonstrates synergy between EGFR inhibitors and T cell checkpoint inhibitors.
  CAS PubMed Google Scholar
• Goel, S. et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471–475 (2017).
  CAS PubMed PubMed Central Google Scholar
• Deng, J. et al. CDK4/6 inhibition augments anti-tumor immunity by enhancing T cell activation. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-17-0915 (2017).
  PubMed PubMed Central Google Scholar
• Vladimer, G. I. et al. Global survey of the immuno-modulatory potential of common drugs. Nat. Chem. Biol. 13, 681–690 (2017). This paper characterizes the 1,024 FDA-approved drugs in a cell–cell interaction assay and demonstrates that up to 10% have effects on the immune system.
  CAS PubMed PubMed Central Google Scholar
• Gould, S. E., Junttila, M. R. & de Sauvage, F. J. Translational value of mouse models in oncology drug development. Nat. Med. 21, 431–439 (2015).
  CAS PubMed Google Scholar
• Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367, 495–507 (2012).
  CAS PubMed Google Scholar
• Wollenhaupt, J. et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J. Rheumatol. 41, 837–852 (2014).
  CAS PubMed Google Scholar
• Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).
  PubMed PubMed Central Google Scholar
• Hernandez-Florez, D. & Valor, L. Protein-kinase inhibitors: a new treatment pathway for autoimmune and inflammatory diseases? Rheumatol. Clin. 12, 91–99 (2016).
  Google Scholar
• Patterson, H., Nibbs, R., McInnes, I. & Siebert, S. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin. Exp. Immunol. 176, 1–10 (2014).
  CAS PubMed PubMed Central Google Scholar
• Villarino, A. V., Kanno, Y. & O'Shea, J. J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 18, 374–384 (2017).
  CAS PubMed Google Scholar
• Schwartz, D. M., Bonelli, M., Gadina, M. & O'Shea, J. J. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12, 25–36 (2016). This Review summarizes the progress in the field of JAK inhibitors for inflammatory disease.
  CAS PubMed Google Scholar
• Kontzias, A., Laurence, A., Gadina, M. & O'Shea, J. J. Kinase inhibitors in the treatment of immune-mediated disease. F1000 Med. Rep. 4, 5 (2012).
  PubMed PubMed Central Google Scholar
• Cohen, P. Targeting protein kinases for the development of anti-inflammatory drugs. Curr. Opin. Cell Biol. 21, 317–324 (2009).
  CAS PubMed Google Scholar
• Weinblatt, M. E. et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N. Engl. J. Med. 363, 1303–1312 (2010).
  CAS PubMed Google Scholar
• Bahjat, F. R. et al. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis Rheum. 58, 1433–1444 (2008).
  CAS PubMed Google Scholar
• Bajpai, M. Fostamatinib, a Syk inhibitor prodrug for the treatment of inflammatory diseases. IDrugs 12, 174–185 (2009).
  CAS PubMed Google Scholar
• Gharwan, H. & Groninger, H. Kinase inhibitors and monoclonal antibodies in oncology: clinical implications. Nat. Rev. Clin. Oncol. 13, 209–227 (2016).
  CAS PubMed Google Scholar
• Rankin, A. L. et al. Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulo-nephritis. J. Immunol. 191, 4540–4550 (2013).
  CAS PubMed Google Scholar
• Evans, E. K. et al. Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J. Pharmacol. Exp. Ther. 346, 219–228 (2013).
  CAS PubMed Google Scholar
• Crofford, L. J., Nyhoff, L. E., Sheehan, J. H. & Kendall, P. L. The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy. Expert Rev. Clin. Immunol. 12, 763–773 (2016).
  CAS PubMed PubMed Central Google Scholar
• Wu, H. et al. Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL-BTK-11 suppresses inflammatory response in rheumatoid arthritis model. Sci. Rep. 7, 466 (2017).
  PubMed PubMed Central Google Scholar
• Burger, J. A. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr. Hematol. Malig. Rep. 9, 44–49 (2014).
  PubMed Google Scholar
• Dudhgaonkar, S. et al. Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity. J. Immunol. 198, 1308–1319 (2017).
  CAS PubMed Google Scholar
• McElroy, W. T. et al. Potent and selective amidopyrazole inhibitors of IRAK4. ACS Med. Chem. Lett. 6, 677–682 (2015).
  CAS PubMed PubMed Central Google Scholar
• Rhyasen, G. W. et al. Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell 24, 90–104 (2013).
  CAS PubMed PubMed Central Google Scholar
• Fiore, M., Forli, S. & Manetti, F. Targeting mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2): medicinal chemistry efforts to lead small molecule inhibitors to clinical trials. J. Med. Chem. 59, 3609–3634 (2016).
  CAS PubMed Google Scholar
• Rommel, C., Camps, M. & Ji, H. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat. Rev. Immunol. 7, 191–201 (2007).
  CAS PubMed Google Scholar
• Boyle, D. L., Kim, H. R., Topolewski, K., Bartok, B. & Firestein, G. S. Novel phosphoinositide 3-kinase delta, gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J. Pharmacol. Exp. Ther. 348, 271–280 (2014).
  PubMed Google Scholar
• Winkler, D. G. et al. PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem. Biol. 20, 1364–1374 (2013).
  CAS PubMed Google Scholar
• Olbrich, P. et al. Activated PI3Kdelta syndrome type 2: two patients, a novel mutation, and review of the literature. Pediatr. Allergy Immunol. 27, 640–644 (2016).
  PubMed Google Scholar
• Hoegenauer, K. et al. Discovery of CDZ173 (leniolisib), representing a structurally novel class of PI3K delta-selective inhibitors. ACS Med. Chem. Lett. 8, 975–980 (2017).
  CAS PubMed PubMed Central Google Scholar
• Rao, V. K. et al. Effective “activated PI3Kdelta syndrome”-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood 130, 2307–2316 (2017).
  CAS PubMed PubMed Central Google Scholar
• Borgel, D. et al. Elevated growth-arrest-specific protein 6 plasma levels in patients with severe sepsis. Crit. Care Med. 34, 219–222 (2006).
  CAS PubMed Google Scholar
• Broad, A., Jones, D. E. & Kirby, J. A. Toll-like receptor (TLR) response tolerance: a key physiological “damage limitation” effect and an important potential opportunity for therapy. Curr. Med. Chem. 13, 2487–2502 (2006).
  CAS PubMed Google Scholar
• Corbett, A. et al. Drug repositioning for Alzheimer's disease. Nat. Rev. Drug Discov. 11, 833–846 (2012).
  CAS PubMed Google Scholar
• McGonigle, P. Animal models of CNS disorders. Biochem. Pharmacol. 87, 140–149 (2014).
  CAS PubMed Google Scholar
• Horvath, P. et al. Screening out irrelevant cell-based models of disease. Nat. Rev. Drug Discov. 15, 751–769 (2016).
  CAS PubMed Google Scholar
• Ghosh, R. et al. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158, 534–548 (2014). This paper validates IRE1α kinase inhibition in models of retinitis pigmentosa and diabetes.
  CAS PubMed PubMed Central Google Scholar
• Meredith, E. L. et al. Discovery of oral VEGFR-2 inhibitors with prolonged ocular retention that are efficacious in models of wet age-related macular degeneration. J. Med. Chem. 58, 9273–9286 (2015). This paper describes a successful preclinical study of a small-molecule VEGFR2 inhibitor for treatment of wet AMD.
  CAS PubMed Google Scholar
• Credle, J. J., Finer-Moore, J. S., Papa, F. R., Stroud, R. M. & Walter, P. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 102, 18773–18784 (2005).
  CAS PubMed Google Scholar
• Zhou, J. et al. The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. Proc. Natl Acad. Sci. USA 103, 14343–14348 (2006).
  CAS PubMed Google Scholar
• Calfon, M. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002).
  CAS PubMed Google Scholar
• Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891 (2001).
  CAS PubMed Google Scholar
• Han, D. et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138, 562–575 (2009).
  CAS PubMed PubMed Central Google Scholar
• Shore, G. C., Papa, F. R. & Oakes, S. A. Signaling cell death from the endoplasmic reticulum stress response. Curr. Opin. Cell Biol. 23, 143–149 (2011).
  CAS PubMed Google Scholar
• Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).
  CAS PubMed Google Scholar
• Moreno, J. A. et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl Med. 5, 206ra138 (2013).
  PubMed Google Scholar
• Radford, H., Moreno, J. A., Verity, N., Halliday, M. & Mallucci, G. R. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 130, 633–642 (2015).
  CAS PubMed PubMed Central Google Scholar
• Axten, J. M. et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 55, 7193–7207 (2012).
  CAS PubMed Google Scholar
• Larhammar, M. et al. Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult. eLife 6, e20725 (2017).
  PubMed PubMed Central Google Scholar
• Patel, S. et al. Scaffold-hopping and structure-based discovery of potent, selective, and brain penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine inhibitors of dual leucine zipper kinase (DLK. MAP3K12). J. Med. Chem. 58, 8182–8199 (2015).
  CAS PubMed Google Scholar
• Patel, S. et al. Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J. Med. Chem. 58, 401–418 (2015).
  CAS PubMed Google Scholar
• Ambati, J. & Fowler, B. J. Mechanisms of age-related macular degeneration. Neuron 75, 26–39 (2012).
  CAS PubMed PubMed Central Google Scholar
• Ishikawa, M., Jin, D., Sawada, Y., Abe, S. & Yoshitomi, T. Future therapies of wet age-related macular degeneration. J. Ophthalmol. 2015, 138070 (2015).
  PubMed PubMed Central Google Scholar
• Appelmann, I., Liersch, R., Kessler, T., Mesters, R. M. & Berdel, W. E. Angiogenesis inhibition in cancer therapy: platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) and their receptors: biological functions and role in malignancy. Recent results in cancer research. Recent Results Cancer Res. 180, 51–81 (2010).
  CAS PubMed Google Scholar
• Diago, T. Jr. et al., Ranibizumab combined with low-dose sorafenib for exudative age-related macular degeneration. Mayo Clin. Proc. 83, 231–234 (2008).
  PubMed PubMed Central Google Scholar
• Slakter, J. S. et al. Phase I/II study of oral pazopanib, a receptor tyrosine kinase inhibitor, in neovascular age related macular degeneration. Invest. Ophthalmol. Visual Sci. 53, 2038 (2012).
  Google Scholar
• Liang, C., Brown, D., Chaudhry, N., Elman, M. & Heier, J. Rationale for treating wet AMD in human using an oral pill consisting of a VEGFR/PDGFR inhibitor X-82. Invest. Ophthalmol. Visual Sci. 54, 3272–3272 (2013).
  Google Scholar
• US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02535286 (2017).
• Mainolfi, N., Karki, R., Liu, F. & Anderson, K. Evolution of a new class of VEGFR-2 inhibitors from scaffold morphing and redesign. ACS Med. Chem. Lett. 7, 363–367 (2016).
  CAS PubMed PubMed Central Google Scholar
• Artac, R. A. et al. Neutralization of vascular endothelial growth factor antiangiogenic isoforms is more effective than treatment with proangiogenic isoforms in stimulating vascular development and follicle progression in the perinatal rat ovary. Biol. Reprod. 81, 978–988 (2009).
  CAS PubMed PubMed Central Google Scholar
• Batson, J. et al. Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease. ACS Chem. Biol. 12, 825–832 (2017).
  CAS PubMed Google Scholar
• Scott, J. D. et al. Discovery of a 3-(4-Pyrimidinyl) indazole (MLi-2), an orally available and selective leucine-rich repeat kinase 2 (LRRK2) inhibitor that reduces brain kinase activity. J. Med. Chem. 60, 2983–2992 (2017).
  CAS PubMed Google Scholar
• Heffron, T. P. et al. Discovery of clinical development candidate GDC-0084, a brain penetrant inhibitor of PI3K and mTOR. ACS Med. Chem. Lett. 7, 351–356 (2016).
  CAS PubMed PubMed Central Google Scholar
• Baltussen, L., Rosianu, F. & Ultanir, S. Kinases in synaptic development and neurological diseases. Prog. Neuropsychopharmacol. Biol. Psychiatry https://doi.org/10.1016/j.pnpbp.2017.12.006 (2017).
  CAS PubMed Google Scholar
• Switon, K., Kotulska, K., Janusz-Kaminska, A., Zmorzynska, J. & Jaworski, J. Molecular neurobiology of mTOR. Neuroscience 341, 112–153 (2017).
  CAS PubMed Google Scholar
• Chan, S. L. & Tan, E. K. Targeting LRRK2 in Parkinson's disease: an update on recent developments. Expert Opin. Ther. Targets 21, 601–610 (2017).
  CAS PubMed Google Scholar
• Lucet, I. S., Tobin, A., Drewry, D., Wilks, A. F. & Doerig, C. Plasmodium kinases as targets for new-generation antimalarials. Future Med. Chem. 4, 2295–2310 (2012).
  CAS PubMed Google Scholar
• McNamara, C. W. et al. Targeting Plasmodium PI(4)K to eliminate malaria. Nature 504, 248–253 (2013). This thorough study validates PfPI(4)K as an antimalarial target.
  CAS PubMed PubMed Central Google Scholar
• Crowther, G. J. et al. Biochemical screening of five protein kinases from Plasmodium falciparum against 14,000 cell-active compounds. PLoS ONE 11, e0149996 (2016).
  PubMed PubMed Central Google Scholar
• Derbyshire, E. R. et al. Chemical interrogation of the malaria kinome. Chembiochem 15, 1920–1930 (2014).
  CAS PubMed PubMed Central Google Scholar
• Carr, J. M., Mahalingam, S., Bonder, C. S. & Pitson, S. M. Sphingosine kinase 1 in viral infections. Rev. Med. Virol. 23, 73–84 (2013).
  CAS PubMed Google Scholar
• Eisa-Beygi, S. & Wen, X. Y. Could pharmacological curtailment of the RhoA/Rho-kinase pathway reverse the endothelial barrier dysfunction associated with Ebola virus infection? Antiviral Res. 114, 53–56 (2015).
  CAS PubMed Google Scholar
• Clark, M. J. et al. GNF-2 inhibits dengue virus by targeting Abl kinases and the viral E protein. Cell Chem. Biol. 23, 443–452 (2016).
  CAS PubMed PubMed Central Google Scholar
• Schreiber, M., Res, I. & Matter, A. Protein kinases as antibacterial targets. Curr. Opin. Cell Biol. 21, 325–330 (2009).
  CAS PubMed Google Scholar
• Gordon, S., Simithy, J., Goodwin, D. C. & Calderon, A. I. Selective Mycobacterium tuberculosis shikimate kinase inhibitors as potential antibacterials. Persp. Med. Chem. 7, 9–20 (2015).
  Google Scholar
• Prisic, S. & Husson, R. N. Mycobacterium tuberculosis serine/threonine protein kinases. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.MGM2-0006-2013 (2014).
• Wang, T. et al. Mtb PKNA/PKNB dual inhibition provides selectivity advantages for inhibitor design to minimize host kinase interactions. ACS Med. Chem. Lett. 8, 1224–1229 (2017).
  CAS PubMed PubMed Central Google Scholar
• Saleh, D. & Degterev, A. Emerging roles for RIPK1 and RIPK3 in Pathogen-induced cell death and host immunity. Curr. Top. Microbiol. Immunol. 403, 37–75 (2017).
  CAS PubMed Google Scholar
• Volpe, G., Panuzzo, C., Ulisciani, S. & Cilloni, D. Imatinib resistance in CML. Cancer Lett. 274, 1–9 (2009).
  CAS PubMed Google Scholar
• Niederst, M. J. & Engelman, J. A. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci. Signal. 6, re6 (2013).
  PubMed Google Scholar
• Smyth, L. A. & Collins, I. Measuring and interpreting the selectivity of protein kinase inhibitors. J. Chem. Biol. 2, 131–151 (2009).
  PubMed PubMed Central Google Scholar
• Miduturu, C. V. et al. High-Throughput Kinase Profiling: A More Efficient Approach towards the Discovery of New Kinase Inhibitors. Chem. Biol. 18, 868–879 (2011).
  CAS PubMed PubMed Central Google Scholar
• Cully, M. Rational drug design: Tuning kinase inhibitor residence time. Nat. Rev. Drug Discov. 14, 457 (2015).
  CAS PubMed Google Scholar
• Zhang, J., Yang, P. L. & Gray, N. S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 9, 28–39 (2009).
  PubMed Google Scholar
• Sang, J. et al. Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov. 3, 430–443 (2013). This paper describes EMAP4–ALK as a highly sensitive client of HSP90, which is preferentially degraded upon HSP90 inhibition.
  CAS PubMed PubMed Central Google Scholar
• Katayama, R. et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc. Natl Acad. Sci. USA 108, 7535–7540 (2011).
  CAS PubMed Google Scholar
• Richards, M. W. et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical beta-propeller domain. Proc. Natl Acad. Sci. USA 111, 5195–5200 (2014).
  CAS PubMed Google Scholar
• Workman, P. & van Montfort, R. EML4-ALK fusions: propelling cancer but creating exploitable chaperone dependence. Cancer Discov. 4, 642–645 (2014).
  CAS PubMed Google Scholar
• Chen, Z. et al. Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Res. 70, 9827–9836 (2010).
  CAS PubMed PubMed Central Google Scholar
• Wang, M. et al. Development of heat shock protein (Hsp90) inhibitors to combat resistance to tyrosine kinase inhibitors through Hsp90-kinase interactions. J. Med. Chem. 59, 5563–5586 (2016).
  CAS PubMed Google Scholar
• Kronke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature 523, 183–188 (2015). This paper uncovers the mechanism of action of lenalidomide in myelodisplastic syndrome.
  CAS PubMed PubMed Central Google Scholar
• Petzold, G., Fischer, E. S. & Thoma, N. H. Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4(CRBN) ubiquitin ligase. Nature 532, 127–130 (2016). This paper characterizes the structural basis for small-molecule-induced CRBN–CKI-α dimerization, providing rationale for development of molecules hijacking this pathway for induced degradation approaches.
  CAS PubMed Google Scholar
• Beke, L. et al. MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells. Biosci. Rep. 35, e00267 (2015).
  PubMed PubMed Central Google Scholar
• Kii, I. et al. Selective inhibition of the kinase DYRK1A by targeting its folding process. Nat. Commun. 7, 11391 (2016).
  CAS PubMed PubMed Central Google Scholar
• Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015).
  CAS PubMed PubMed Central Google Scholar
• Kritzer, J. New Frontiers in Chemical Biology: Enabling Drug Discovery. Edited by Mark E. Bunnage. ChemMedChem 6, 1747–1748 (2011).
  CAS Google Scholar
• Buckley, D. L. & Crews, C. M. Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system. Angew. Chem. Int. Ed. 53, 2312–2330 (2014).
  CAS Google Scholar
• Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017). This paper provides an extensive and up-to-date review of the PROTAC field.
  CAS PubMed Google Scholar
• Toure, M. & Crews, C. M. Small-molecule PROTACS: new approaches to protein degradation. Angew. Chem. Int. Ed. 55, 1966–1973 (2016).
  CAS Google Scholar
• Henning, R. K. et al. Degradation of Akt using protein-catalyzed capture agents. J. Pept. Sci. 22, 196–200 (2016).
  CAS PubMed PubMed Central Google Scholar
• Lai, A. C. et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed. 55, 807–810 (2016).
  CAS Google Scholar
• Hines, J., Gough, J. D., Corson, T. W. & Crews, C. M. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc. Natl Acad. Sci. USA 110, 8942–8947 (2013).
  CAS PubMed Google Scholar
• Crew, A. P. et al. Identification and characterization of Von Hippel-Lindau-recruiting proteolysis targeting chimeras (PROTACs) of TANK-binding kinase 1. J. Med. Chem. 61, 583–598 (2018).
  CAS PubMed Google Scholar
• Robb, C. M. et al. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem. Commun. 53, 7577–7580 (2017).
  CAS Google Scholar
• Olson, C. M. et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat. Chem. Biol. 14, 163–170 (2018).
  CAS PubMed Google Scholar
• Xie, T. et al. Pharmacological targeting of the pseudokinase Her3. Nat. Chem. Biol. 10, 1006–1012 (2014).
  CAS PubMed PubMed Central Google Scholar
• Chan, K. H., Zengerle, M., Testa, A. & Ciulli, A. Impact of target warhead and linkage vector on inducing protein degradation: comparison of bromodomain and extra-terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds. J. Med. Chem. 61, 504–513 (2018).
  CAS PubMed Google Scholar
• Gadd, M. S. et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514–521 (2017).
  CAS PubMed PubMed Central Google Scholar
• Matyskiela, M. E. et al. Cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J. Med. Chem. 61, 535–542 (2018).
  CAS PubMed Google Scholar
• Hansen, J. D. et al. Protein degradation via CRL4CRBN ubiquitin ligase: discovery and structure-activity relationships of novel glutarimide analogs that promote degradation of Aiolos and/or GSPT1. J. Med. Chem. 61, 492–503 (2018).
  CAS PubMed Google Scholar
• Huang, H. T. et al. Chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem. Biol. 25, 88–99.e6 (2018).
  CAS PubMed Google Scholar
• Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87.e5 (2018).
  CAS PubMed Google Scholar
• Yang, C. et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 36, 2255–2264 (2017).
  CAS PubMed Google Scholar
• Herrera-Abreu, M. T. et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 76, 2301–2313 (2016).
  CAS PubMed PubMed Central Google Scholar
• Taavi, K. et al. An oral androgen receptor PROTAC degrader for prostate cancer [abstract]. J. Clin. Oncol. 35 (Suppl.), 273 (2017).
  Google Scholar
• Leestemaker, Y. et al. Proteasome activation by small molecules. Cell Chem. Biol. 24, 725–736.e7 (2017).
  CAS PubMed Google Scholar
• Liu, Q. et al. Developing irreversible inhibitors of the protein kinase cysteinome. Chem. Biol. 20, 146–159 (2013).
  PubMed PubMed Central Google Scholar
• Chaikuad, A., Koch, P., Laufer, S. & Knapp, S. Targeting the protein kinases cysteinome. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.201707875 (2017).
  CAS PubMed Google Scholar
• Fischer, P. M. Approved and experimental small-molecule oncology kinase inhibitor drugs: a mid-2016 overview. Med. Res. Rev. 37, 314–367 (2017).
  PubMed Google Scholar
• Strelow, J. M. A Perspective on the Kinetics of Covalent and Irreversible Inhibition. SLAS Discov. 22, 3–20 (2017).
  CAS PubMed Google Scholar
• Copeland, R. A. Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists. Methods Biochem. Anal. 46, 1–265 (2005).
  PubMed Google Scholar
• Mohutsky, M. & Hall, S. D. Irreversible enzyme inhibition kinetics and drug-drug interactions. Methods Mol. Biol. 1113, 57–91 (2014).
  CAS PubMed Google Scholar
• Schwartz, P. A. et al. Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance. Proc. Natl Acad. Sci. USA 111, 173–178 (2014).
  CAS PubMed Google Scholar
• Zaro, B. W., Whitby, L. R., Lum, K. M. & Cravatt, B. F. Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors. J. Am. Chem. Soc. 138, 15841–15844 (2016). This paper describes a novel cysteine targeting warhead with improved on-target selectivity.
  CAS PubMed PubMed Central Google Scholar
• Serafimova, I. M. et al. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat. Chem. Biol. 8, 471–476 (2012).
  CAS PubMed PubMed Central Google Scholar
• Krishnan, S. et al. Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis. J. Am. Chem. Soc. 136, 12624–12630 (2014).
  CAS PubMed PubMed Central Google Scholar
• Bradshaw, J. M. et al. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol. 11, 525–531 (2015). This paper reports a method for rational design of drug residence times via reversible covalent interactions.
  CAS PubMed PubMed Central Google Scholar
• Forster, M. et al. Selective JAK3 inhibitors with a covalent reversible binding mode targeting a new induced fit binding pocket. Cell Chem. Biol. 23, 1335–1340 (2016).
  CAS PubMed PubMed Central Google Scholar
• London, N. et al. Covalent docking of large libraries for the discovery of chemical probes. Nat. Chem. Biol. 10, 1066–1072 (2014).
  CAS PubMed PubMed Central Google Scholar
• Miller, R. M., Paavilainen, V. O., Krishnan, S., Serafimova, I. M. & Taunton, J. Electrophilic fragment-based design of reversible covalent kinase inhibitors. J. Am. Chem. Soc. 135, 5298–5301 (2013).
  CAS PubMed PubMed Central Google Scholar
• Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016). This paper uses reactive fragments to enumerate the targetable cysteine residues in the proteome.
  CAS PubMed PubMed Central Google Scholar
• Anscombe, E. et al. Identification and characterization of an irreversible inhibitor of CDK2. Chem. Biol. 22, 1159–1164 (2015).
  CAS PubMed PubMed Central Google Scholar
• Lin, S. et al. Redox-based reagents for chemoselective methionine bioconjugation. Science 355, 597–602 (2017).
  CAS PubMed PubMed Central Google Scholar
• Dalton, S. E. et al. Selectively targeting the kinome-conserved lysine of PI3Kdelta as a general approach to covalent kinase inhibition. J. Am. Chem. Soc. 140, 932–939 (2018).
  CAS PubMed Google Scholar
• Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7, 583–590 (2008).
  CAS PubMed PubMed Central Google Scholar
• Greggio, E. & Cookson, M. R. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 1, e00002 (2009).
  PubMed PubMed Central Google Scholar
• Kumar, A. & Cookson, M. R. Role of LRRK2 kinase dysfunction in Parkinson disease. Expert Rev. Mol. Med. 13, e20 (2011).
  PubMed PubMed Central Google Scholar
• West, A. B. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp. Neurol. 298, 236–245 (2017).
  CAS PubMed PubMed Central Google Scholar
• Lee, K. L. et al. Discovery of clinical candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a potent, selective inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4), by fragment-based drug design. J. Med. Chem. 60, 5521–5542 (2017).
  CAS PubMed Google Scholar
• Gomez, N., Erazo, T. & Lizcano, J. M. ERK5 and cell proliferation: nuclear localization is what matters. Front. Cell Dev. Biol. 4, 105 (2016).
  PubMed PubMed Central Google Scholar
• Hoang, V. T. et al. Oncogenic signaling of MEK5-ERK5. Cancer Lett. 392, 51–59 (2017).
  CAS PubMed PubMed Central Google Scholar
• Lin, E. C. et al. ERK5 kinase activity is dispensable for cellular immune response and proliferation. Proc. Natl Acad. Sci. USA 113, 11865–11870 (2016).
  CAS PubMed Google Scholar
• Deng, X. et al. Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a potent and selective inhibitor of big MAP kinase 1. ACS Med. Chem. Lett. 2, 195–200 (2011).
  CAS PubMed PubMed Central Google Scholar
• Deng, X. et al. Structural determinants for ERK5 (MAPK7) and leucine rich repeat kinase 2 activities of benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones. Eur. J. Med. Chem. 70, 758–767 (2013).
  CAS PubMed PubMed Central Google Scholar
• Elkins, J. M. et al. X-Ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor. J. Med. Chem. 56, 4413–4421 (2013).
  CAS PubMed PubMed Central Google Scholar
• Berger, S. B. et al. Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014).
  CAS PubMed PubMed Central Google Scholar
• Harris, P. A. et al. DNA-encoded library screening identifies benzo[b][1,4]oxazepin-4-ones as highly potent and monoselective receptor interacting protein 1 kinase inhibitors. J. Med. Chem. 59, 2163–2178 (2016).
  CAS PubMed Google Scholar
• Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).
  CAS PubMed Google Scholar
• Goldstein, D. M., Gray, N. S. & Zarrinkar, P. P. High-throughput kinase profiling as a platform for drug discovery. Nat. Rev. Drug Discov. 7, 391–397 (2008).
  CAS PubMed Google Scholar
• Nomura, D. K., Dix, M. M. & Cravatt, B. F. Activity-based protein profiling for biochemical pathway discovery in cancer. Nat. Rev. Cancer 10, 630–638 (2010).
  CAS PubMed PubMed Central Google Scholar
• Patricelli, M. P. et al. In situ kinase profiling reveals functionally relevant properties of native kinases. Chem. Biol. 18, 699–710 (2011).
  CAS PubMed PubMed Central Google Scholar
• Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat. Biotechnol. 25, 1035–1044 (2007).
  CAS PubMed Google Scholar
• Medard, G. et al. Optimized chemical proteomics assay for kinase inhibitor profiling. J. Proteome Res. 14, 1574–1586 (2015).
  CAS PubMed Google Scholar
• Golkowski, M. et al. Kinobead and single-shot LC-MS profiling identifies selective PKD inhibitors. J. Proteome Res. 16, 1216–1227 (2017).
  CAS PubMed PubMed Central Google Scholar
• Vasta, J. D. et al. Quantitative, wide-spectrum kinase profiling in live cells for assessing the effect of cellular ATP on target engagement. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2017.10.010 (2017). This paper describes a commercially available, in cell competition assay to discern kinase inhibitor selectivity in a physiological context.
  PubMed PubMed Central Google Scholar
• Munoz, L. Non-kinase targets of protein kinase inhibitors. Nat. Rev. Drug Discov. 16, 424–440 (2017). This article is an overview of unexpected off-target activities that have been discovered in kinase inhibitors.
  CAS PubMed Google Scholar
• Ciceri, P. et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat. Chem. Biol. 10, 305–312 (2014).
  CAS PubMed PubMed Central Google Scholar
• Ember, S. W. et al. Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. ACS Chem. Biol. 9, 1160–1171 (2014).
  CAS PubMed PubMed Central Google Scholar
• Rimassa, L., Bruix, J., Broggini, M. & Santoro, A. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET — letter. Clin. Cancer Res. 19, 4290 (2013).
  CAS PubMed Google Scholar
• Katayama, R. et al. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res. 73, 3087–3096 (2013).
  CAS PubMed PubMed Central Google Scholar
• Cheong, J. K. et al. IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1delta/varepsilon and Wnt/beta-catenin independent inhibition of mitotic spindle formation. Oncogene 30, 2558–2569 (2011).
  CAS PubMed PubMed Central Google Scholar
• Lanning, B. R. et al. A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors. Nat. Chem. Biol. 10, 760–767 (2014). This paper describes pull-down proteomics inhibitor profiling methods for assessing the proteome-wide selectivity of covalent inhibitors.
  CAS PubMed PubMed Central Google Scholar
• Niphakis, M. J. & Cravatt, B. F. Enzyme inhibitor discovery by activity-based protein profiling. Annu. Rev. Biochem. 83, 341–377 (2014).
  CAS PubMed Google Scholar
• Yang, P. & Liu, K. Activity-based protein profiling: recent advances in probe development and applications. Chembiochem 16, 712–724 (2015).
  CAS PubMed Google Scholar
• Wang, K. et al. Chemistry-based functional proteomics for drug target deconvolution. Expert Rev. Proteom. 9, 293–310 (2012).
  CAS Google Scholar
• Martinez Molina, D. et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341, 84–87 (2013).
  PubMed Google Scholar
• Klaeger, S. et al. Chemical proteomics reveals ferrochelatase as a common off-target of kinase inhibitors. ACS Chem. Biol. 11, 1245–1254 (2016).
  CAS PubMed Google Scholar
• Reinhard, F. B. et al. Thermal proteome profiling monitors ligand interactions with cellular membrane proteins. Nat. Methods 12, 1129–1131 (2015).
  CAS PubMed Google Scholar
• Kooistra, A. J. et al. KLIFS: a structural kinase-ligand interaction database. Nucleic Acids Res. 44, D365–D371 (2016).
  CAS PubMed Google Scholar
• Isberg, V. et al. GPCRdb: an information system for G protein-coupled receptors. Nucleic Acids Res. 44, D356–D364 (2016).
  CAS PubMed Google Scholar
• McGuire, R. et al. 3D-e-Chem-VM: structural cheminformatics research infrastructure in a freely available virtual machine. J. Chem. Inform. Model. 57, 115–121 (2017).
  CAS Google Scholar
• Lin, X. et al. Life beyond kinases: structure-based discovery of sorafenib as nanomolar antagonist of 5-HT receptors. J. Med. Chem. 55, 5749–5759 (2012).
  CAS PubMed PubMed Central Google Scholar
• Merget, B., Turk, S., Eid, S., Rippmann, F. & Fulle, S. Profiling prediction of kinase inhibitors: toward the virtual assay. J. Med. Chem. 60, 474–485 (2017).
  CAS PubMed Google Scholar
• [No authors listed.] Kinase Assay Tools. Reaction Biology Corp. http://www.reactionbiology.com/webapps/site/KinaseDetail.aspx (2016).
• Drewry, D. H. et al. Progress towards a public chemogenomic set for protein kinases and a call for contributions. PLoS ONE 12, e0181585 (2017).
  PubMed PubMed Central Google Scholar
• Klaeger, S. et al. The target landscape of clinical kinase drugs. Science 358, eaan4368 (2017).
  PubMed PubMed Central Google Scholar
• Leelananda, S. P. & Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem. 12, 2694–2718 (2016).
  CAS PubMed PubMed Central Google Scholar
• Li, Z. & Lazaridis, T. Thermodynamic contributions of the ordered water molecule in HIV-1 protease. J. Am. Chem. Soc. 125, 6636–6637 (2003).
  CAS PubMed Google Scholar
• Huggins, D. J., Quantifying the entropy of binding for water molecules in protein cavities by computing correlations. Biophys. J. 108, 928–936 (2015).
  CAS PubMed PubMed Central Google Scholar
• Li, Z. & Lazaridis, T. Computing the thermodynamic contributions of interfacial water. Methods Mol. Biol. 819, 393–404 (2012).
  CAS PubMed Google Scholar
• Robinson, D. D., Sherman, W. & Farid, R. Understanding kinase selectivity through energetic analysis of binding site waters. ChemMedChem 5, 618–627 (2010).
  CAS PubMed Google Scholar
• Abel, R., Young, T., Farid, R., Berne, B. J. & Friesner, R. A. Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J. Am. Chem. Soc. 130, 2817–2831 (2008).
  CAS PubMed PubMed Central Google Scholar
• Young, T., Abel, R., Kim, B., Berne, B. J. & Friesner, R. A. Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding. Proc. Natl Acad. Sci. USA 104, 808–813 (2007).
  CAS PubMed Google Scholar
• Kitamura, K. et al. Binding free-energy calculation is a powerful tool for drug optimization: calculation and measurement of binding free energy for 7-azaindole derivatives to glycogen synthase kinase-3beta. J. Chem. Inform. Model. 54, 1653–1660 (2014). This study is an elegant example of the accuracy of FEP calculations in ranking kinase inhibitors.
  CAS Google Scholar
• Lin, Y. L., Meng, Y., Jiang, W. & Roux, B. Explaining why Gleevec is a specific and potent inhibitor of Abl kinase. Proc. Natl Acad. Sci. USA 110, 1664–1669 (2013).
  CAS PubMed Google Scholar
• Araki, M. et al. The effect of conformational flexibility on binding free energy estimation between kinases and their inhibitors. J. Chem. Inform. Model. 56, 2445–2456 (2016).
  CAS Google Scholar
• Ruiz-Carmona, S. et al. Dynamic undocking and the quasi-bound state as tools for drug discovery. Nat. Chem. 9, 201–206 (2017). This paper describes a new method for virtual screening and ranking ligands on the basis of calculations of nonthermodynamic properties.
  CAS PubMed Google Scholar
• Takeuchi, K. & Ito, F. Receptor tyrosine kinases and targeted cancer therapeutics. Biol. Pharm. Bull. 34, 1774–1780 (2011).
  CAS PubMed Google Scholar
• Mushtaq, G. et al. Neuroprotective mechanisms mediated by CDK5 inhibition. Curr. Pharm. Design 22, 527–534 (2016).
  CAS Google Scholar
• US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02784106 (2017).
• US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01882803 (2017).
• US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02100852 (2017).
• US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01674569 (2017).
• Narayanan, A. & Jones, L. H. Sulfonyl fluorides as privileged warheads in chemical biology. Chem. Sci. 6, 2650–2659 (2015).
  CAS PubMed PubMed Central Google Scholar
• Morales-Sanfrutos, J. et al. Vinyl sulfone: a versatile function for simple bioconjugation and immobilization. Org. Biomol. Chem. 8, 667–675 (2010).
  CAS PubMed Google Scholar
• Garcia, F. J. & Carroll, K. S. Redox-based probes as tools to monitor oxidized protein tyrosine phosphatases in living cells. Eur. J. Med. Chem. 88, 28–33 (2014).
  CAS PubMed Google Scholar
• Leonard, S. E., Garcia, F. J., Goodsell, D. S. & Carroll, K. S. Redox-based probes for protein tyrosine phosphatases. Angew. Chem. Int. Ed. 50, 4423–4427 (2011).
  CAS Google Scholar
• Wani, R. et al. Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species. Proc. Natl Acad. Sci. USA 108, 10550–10555 (2011).
  CAS PubMed Google Scholar