Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. 1993

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The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer

A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure–activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound <b>49</b> achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds <b>36</b> and <b>49</b> show favorable potency and PK characteristics in preclinical species indicative of suitability for further development

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

© 2020 The Authors Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC. In the pursuit of hormone receptor modulators in prostate cancer, a potent, ultraselective CDK9 inhibitor is discovered. This study describes the most selective inhibitors of CDK9 known to date and provides compelling preclinical in vitro and in vivo support for CDK9 as a therapeutic target