When JAKi meet HDACi: Design and Synthesis of novel Dual Inhibitors for Leukaemia Therapy (original) (raw)
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Discovery of highly potent, selective, covalent inhibitors of JAK3
Bioorganic & medicinal chemistry letters, 2017
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
De Novo Designing of HDAC inhibitors in cancer therapy
HDACs are enzymes found in eukaryotes. It removes the acetyl group from the lysine residue on the N-terminal regions of histone proteins and the process is called histone deacetylation. It results in the increased positive charge on histones. The DNA possesses negatively charged sugar-phosphate backbone; therefore the positively charged histones bind more firmly to the DNA. This makes the DNA unavailable for the transcription factors and eventually leads to the gene silencing. Rather than histone proteins, HDACs are often associated with the deacetylation of p53, GATA II etc. At a certain level deacetylation is necessary for the control of gene expression regulation. When the HDACs are over expressed it will result in the silencing of some growth regulator genes and tumor suppressor genes, which results in cancer. HDACs have been studied recently as the target for designing anticancer drugs. In this study a number of HDAC structures have been collected and novel inhibitors have been designed using the fragment based drug designing strategy. The present work suggests some HDAC inhibitor molecules to be considered as a potent drug for cancer treatment in future.
Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates
Molecules
The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies...
In silico identification of natural product inhibitors of JAK2
Methods (San Diego, Calif.), 2015
Emodic acid (1) and 6-chloroemodic acid (2) have been identified from a natural product database as useful scaffolds for the future development of novel JAK2 inhibitors using structure-based high-throughput virtual screening. Low-energy binding conformations of 1 and 2 in the JAK2 PTK domain were generated by virtual ligand docking and were found to overlap considerably with the binding pose of CMP6, a known JAK2 inhibitor. Compounds 1 and 2 displayed low micromolar efficacies against JAK2 enzyme activity and JAK2 autophosphorylation in human erythroleukemia cells, and inhibited STAT3 DNA-binding activity in a human hepatocarcinoma cell line.
Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585
British Journal of Haematology, 2010
Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti-cancer agents and may be useful to enhance the therapeutic efficiency of established anti-myeloma treatments. This study preclinically evaluated the effects of the 'second generation' pan-HDAC inhibitor JNJ-26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n = 42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl-1 depletion and Hsp72 induction were the most reliable features observed in JNJ-26481585-treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ-26481585 with anti-myeloma therapeutic agents generally resulted in effects close to additivity. In view of the favourable activity of this novel HDAC-inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.
ACS Medicinal Chemistry Letters, 2015
JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.
Journal of medicinal chemistry, 2017
The discovery of a potent selective low dose JAK1 inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.
Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol
Journal of Biological Chemistry, 2014
Background: Janus kinase 3 (Jak3) inhibitors hold promise for treatment of autoimmunity, but developing selective inhibitors is challenging. Results: We designed Jak3 inhibitors that avoid inhibition of the other JAKs. Conclusion: Our inhibitors possess high selectivity against other kinases and can potently inhibit Jak3 activity in cell-based assays. Significance: This class of irreversible inhibitors may be useful as selective agents of Jak3 inhibition. The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC 50 < 100 nM) inhibit Jak3 activity in cellbased assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.