91007-16-8Relevant articles and documents
Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors
Richters, André,Doyle, Shelby K.,Freeman, David B.,Lee, Christina,Leifer, Becky S.,Jagannathan, Sajjeev,Kabinger, Florian,Koren, Jo?t Vrabi?,Struntz, Nicholas B.,Urgiles, Julie,Stagg, Ryan A.,Curtin, Brice H.,Chatterjee, Deep,Mathea, Sebastian,Mikochik, Peter J.,Hopkins, Tamara D.,Gao, Hua,Branch, Jonathan R.,Xin, Hong,Westover, Lori,Bignan, Gilles C.,Rupnow, Brent A.,Karlin, Kristen L.,Olson, Calla M.,Westbrook, Thomas F.,Vacca, Joseph,Wilfong, Chris M.,Trotter, B. Wesley,Saffran, Douglas C.,Bischofberger, Norbert,Knapp, Stefan,Russo, Joshua W.,Hickson, Ian,Bischoff, James R.,Gottardis, Marco M.,Balk, Steven P.,Lin, Charles Y.,Pop, Marius S.,Koehler, Angela N.
, p. 134 - 14,147 (2021)
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.
Mild decarboxylative activation of malonic acid derivatives by 1,1′-carbonyldiimidazole
Lafrance, Danny,Bowles, Paul,Leeman, Kyle,Rafka, Robert
supporting information; experimental part, p. 2322 - 2325 (2011/06/26)
Chemical equations presented. Malonic acid derivatives undergo unusually mild decarboxylation when treated with N,N′-carbonyldiimidazole (CDI) at room temperature to generate the carbonyl imidazole moiety in high yield, which can be reacted further with a variety of nucleophiles in an efficient one-pot process.
