Protein methyltransferases as a target class for drug discovery (original) (raw)

• Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
  Article CAS Google Scholar
• Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007). A thorough overview of post-translational modifications on core histones, the enzymes that mediate these modifications and the biological functions of the modification.
  Article CAS Google Scholar
• Smith, B. C. & Denu, J. M. Chemical mechanisms of histone lysine and arginine modifications. Biochim. Biophys. Acta 1789, 45–57 (2008). An excellent review of the chemical biology of lysine- and arginine-modifying enzymes.
  Article Google Scholar
• Cole, P. A. Chemical probes for histone-modifying enzymes. Nature Chem. Biol. 4, 590–597 (2008).
  Article CAS Google Scholar
• Keppler, B. R. & Archer, T. K. Chromatin-modifying enzymes as therapeutic targets — Part 1. Expert Opin. Ther. Targets. 12, 1301–1312 (2008).
  Article CAS Google Scholar
• Pray, L. At the flick of a switch: epigenetic drugs. Chem. Biol. 15, 640–641 (2008).
  Article CAS Google Scholar
• Jones, P. A. & Baylin, S. B. The epigenomics of cancer. Cell 128, 683–692 (2007).
  Article CAS Google Scholar
• Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nature Rev. Immunol. 9, 91–105 (2009).
  Article CAS Google Scholar
• Tsankova, N., Renthal, W., Kumar, A. & Nestler, E. J. Epigenetic regulation in psychiatric disorders. Nature Rev. Neurosci. 8, 355–367 (2007).
  Article CAS Google Scholar
• Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).
  Article CAS Google Scholar
• Krivtsov, A. V. et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14, 355–368 (2008).
  Article CAS Google Scholar
• Jansson, M. et al. Arginine methylation regulates the p53 response. Nature Cell Biol. 10, 1431–1439 (2008).
  Article CAS Google Scholar
• Hong, H. et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer 101, 83–89 (2004).
  Article CAS Google Scholar
• Schneider, R., Bannister, A. J. & Kouzarides, T. Unsafe SETs: histone lysine methyltransferases and cancer. Trends Biochem. Sci. 27, 396–402 (2002).
  Article CAS Google Scholar
• Simon, J. A. & Lange, C. A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21–29 (2008).
  Article CAS Google Scholar
• Dillon, S. C., Zhang, X., Trievel, R. C. & Cheng, X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 6, 227 (2005).
  Article Google Scholar
• Ryu, H. et al. ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease. Proc. Natl Acad. Sci. USA 103, 19176–19181 (2006).
  Article CAS Google Scholar
• Cheng, D., Cote, J., Shaaban, S. & Bedford, M. T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol. Cell 25, 71–83 (2007).
  Article Google Scholar
• Li, Y. et al. Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-κB-dependent inflammatory genes. Relevance to diabetes and inflammation. J. Biol. Chem. 283, 26771–26781 (2008).
  Article CAS Google Scholar
• Covic, M. et al. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-κB-dependent gene expression. EMBO J. 24, 85–96 (2005).
  Article CAS Google Scholar
• Hassa, P. O., Covic, M., Bedford, M. T. & Hottiger, M. O. Protein arginine methyltransferase 1 coactivates NF-κB-dependent gene expression synergistically with CARM1 and PARP1. J. Mol. Biol. 377, 668–678 (2008).
  Article CAS Google Scholar
• Huang, J. et al. Trimethylation of histone H3 lysine 4 by Set1 in the lytic infection of human herpes simplex virus 1. J. Virol. 80, 5740–5746 (2006).
  Article CAS Google Scholar
• Jeong, S. J. et al. Coactivator-associated arginine methyltransferase 1 enhances transcriptional activity of the human T-cell lymphotropic virus type 1 long terminal repeat through direct interaction with Tax. J. Virol. 80, 10036–10044 (2006).
  Article CAS Google Scholar
• Cheng, X., Collins, R. E. & Zhang, X. Structural and sequence motifs of protein (histone) methylation enzymes. Annu. Rev. Biophys. Biomol. Struct. 34, 267–294 (2005).
  Article CAS Google Scholar
• Goldstein, D. M., Gray, N. S. & Zarrinkar, P. P. High-throughput kinase profiling as a platform for drug discovery. Nature Rev. Drug Discov. 7, 391–397 (2008).
  Article CAS Google Scholar
• Mook, R. A. The importance and complexity of target class selectivity in drug discovery. The American Association for Cancer Research Education Book 223–226 (The American Association for Cancer Research, Philadelphia, 2005).
  Google Scholar
• Copeland, R. A. Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists (Wiley, Hoboken, 2005).
  Google Scholar
• Cheng, D. et al. Small molecule regulators of protein arginine methyltransferases. J. Biol. Chem. 279, 23892–23899 (2004).
  Article CAS Google Scholar
• Allis, C. D. et al. New nomenclature for chromatin-modifying enzymes. Cell 131, 633–636 (2007).
  Article CAS Google Scholar
• Zhang, X. & Bruice, T. C. Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases. Proc. Natl Acad. Sci. USA 105, 5728–5732 (2008). This work provides a detailed theoretical basis to explain the substrate specificity of the protein lysine methyltransferases.
  Article CAS Google Scholar
• Fedorov, O. et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl Acad. Sci. USA 104, 20523–20528 (2007).
  Article CAS Google Scholar
• Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech. 26, 127–132 (2008).
  Article CAS Google Scholar
• Min, J., Feng, Q., Li, Z., Zhang, Y. & Xu, R. M. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112, 711–723 (2003).
  Article CAS Google Scholar
• Sawada, K. et al. Structure of the conserved core of the yeast Dot1p, a nucleosomal histone H3 lysine 79 methyltransferase. J. Biol. Chem. 279, 43296–43306 (2004).
  Article CAS Google Scholar
• Copeland, R. A. Enzymes: A Practical Introduction to Structure, Mechanism and Data Analysis 2nd edn (Wiley, Hoboken, 2000).
  Book Google Scholar
• Couture, J. F., Hauk, G., Thompson, M. J., Blackburn, G. M. & Trievel, R. C. Catalytic roles for carbon–oxygen hydrogen bonding in SET domain lysine methyltransferases. J. Biochem. 281, 19280–19287 (2006).
  CAS Google Scholar
• Collins, R. E. et al. In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J. Biol. Chem. 280, 5563–5570 (2005). This study provides a structural basis for the wide range of lysine methylation patterns that is achieved by different SET domain PKMTs.
  Article CAS Google Scholar
• Trievel, R. C., Flynn, E. M., Houtz, R. L. & Hurley, J. H. Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT. Nature Struct. Biol. 10, 545–552 (2003).
  Article CAS Google Scholar
• Zhang, X. et al. Structural basis for the product specificity of histone lysine methyltransferases. Mol. Cell 12, 177–185 (2003).
  Article Google Scholar
• Frederiks, F. et al. Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states. Nature Struct. Mol. Biol. 15, 550–557 (2008).
  Article CAS Google Scholar
• Chiang, P. K. Biological effects of inhibitors of S-adenosylhomocysteine hydrolase. Pharmacol. Ther. 77, 115–134 (1998).
  Article CAS Google Scholar
• Bender, C. M., Zingg, J.-M. & Jones, P. A. DNA methylation as a target for drug design. Pharm. Res. 15, 175–187 (1998).
  Article CAS Google Scholar
• Fiskus, W. et al. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol. Ther. 8, 939–950 (2009).
  Article CAS Google Scholar
• Chang, Y. et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nature Struct. Mol. Biol. 16, 312–317 (2009).
  Article CAS Google Scholar
• Allan, M. et al. _N_-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1 _H_-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 19, 1218–1223 (2009). The first examples of potent, drug-like inhibitors of a human PMT.
  Article CAS Google Scholar
• Purandare, A. V. et al. Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 18, 4438–4441 (2008).
  Article CAS Google Scholar
• Huynh, T. et al. Optimization of pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med. Chem. Lett. 19, 2924–2927 (2009).
  Article CAS Google Scholar
• Copeland, R. A., Gontarek, R. & Luo, L. in Textbook of Drug Design and Discovery 4th edn Ch. 12 (eds. Krogsgaard-Larsen, P., Madsen, U. & Stromgaard, K.) 378–407 (Taylor and Francis, New York, 2009).
  Google Scholar
• Troffer-Charlier, N., Cura, V., Hassenboehler, P., Moras, D. & Cavarelli, J. Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains. EMBO J. 26, 4391–4401 (2007).
  Article CAS Google Scholar
• Couture, J.-F., Collazo, E., Brunzelle, J. S. & Trievel, R. C. Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 19, 1455–1465 (2005).
  Article CAS Google Scholar
• Ma, W. W. & Adjei, A. A. Novel agents on the horizon for cancer therapy. CA Cancer J. Clin. 59, 111–137 (2009). A review of the current knowledge on how aberrant epigenetic mechanisms can contribute to the development of cancer and the progress in developing therapies that target these mechanisms.
  Article Google Scholar
• Cortez, C. C. & Jones, P. A. Chromatin, cancer and drug therapies. Mutat. Res. 647, 44–51 (2008).
  Article CAS Google Scholar
• Kang, M. Y. et al. Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer. Int. J. Cancer 121, 2192–2197 (2007).
  Article CAS Google Scholar
• Watanabe, H. et al. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int. 8, 15 (2008).
  Article Google Scholar
• Kondo, Y. et al. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS One 3, e2037 (2008).
  Article Google Scholar
• Tkachuk, D., Kohler, S. & Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691–700 (1992).
  Article CAS Google Scholar
• Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701–708 (1992).
  Article CAS Google Scholar
• Liedtke, M. & Cleary, M. L. Therapeutic targeting of MLL. Blood 113, 6061–6068 (2009).
  Article CAS Google Scholar
• Wang, G. G., Cai, L., Pasillas, M. P. & Kamps, M. P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature Cell Biol. 9, 804–812 (2007).
  Article CAS Google Scholar
• Marango, J. et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 111, 3145–3154 (2008).
  Article CAS Google Scholar
• Kim, J. Y. et al. Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol. Cell Biol. 28, 2023–2034 (2008).
  Article CAS Google Scholar
• Lauring, J. et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 111, 856–864 (2008).
  Article CAS Google Scholar
• Angrand, P. O. et al. NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Genomics 74, 79–88 (2001).
  Article CAS Google Scholar
• Rosati, R. et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99, 3857–3860 (2002).
  Article CAS Google Scholar
• Tonon, G. et al. High-resolution genomic profiles of human lung cancer. Proc. Natl Acad. Sci. USA 102, 9625–9630 (2005).
  Article CAS Google Scholar
• Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).
  Article CAS Google Scholar
• Bitoun, E., Oliver, P. L. & Davies, K. E. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum. Mol. Genet. 16, 92–106 (2007).
  Article CAS Google Scholar
• Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nature Cell Biol. 6, 731–740 (2004).
  Article CAS Google Scholar
• Hamamoto, R. et al. Enhanced SMYD3 expression is essential for the growth of breast cancer cells. Cancer Sci. 97, 113–118 (2006).
  Article CAS Google Scholar
• Bracken, A. P. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 22, 5323–5335 (2003).
  Article CAS Google Scholar
• Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).
  Article CAS Google Scholar
• Subramanian, K. et al. Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase. Mol. Cell 30, 336–347 (2008).
  Article CAS Google Scholar
• Nishikawa, N. et al. Gene amplification and overexpression of PRDM14 in breast cancers. Cancer Res. 67, 9649–9657 (2007).
  Article CAS Google Scholar
• Majumder, S., Liu, Y., Ford, O. H., 3rd, Mohler, J. L. & Whang, Y. E. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate 66, 1292–1301 (2006).
  Article CAS Google Scholar
• Frietze, S., Lupien, M., Silver, P. A. & Brown, M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res. 68, 301–306 (2008).
  Article CAS Google Scholar
• Zhao, Q. et al. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nature Struct. Mol. Biol. 16, 304–311 (2009).
  Article CAS Google Scholar
• Patnaik, D. et al. Substrate specificity and kinetic mechanism of mammalian G9a histone H3 methyltransferase. J. Biol. Chem. 279, 53248–53258 (2004).
  Article CAS Google Scholar
• Chin, H. G., Patnaik, D., Esteve, P.-O., Jacobsen, S. E. & Pradhan, S. Catalytic properties and kinetic mechanism of human recombinant lys-9 histone H3 methyltransferase SUV39H1: participation of the chromodomain in enzymatic catalysis. Biochemistry 45, 3272–3284 (2006).
  Article CAS Google Scholar
• Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3–9. Nature Chem. Biol. 1, 143–145 (2005).
  Article CAS Google Scholar
• Kubicek, S. et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25, 473–481 (2007).
  Article CAS Google Scholar