| Literature DB >> 33306391 |
Bernard Barlaam1, Robert Casella2, Justin Cidado3, Calum Cook4, Chris De Savi3, Allan Dishington1, Craig S Donald1, Lisa Drew3, Andrew D Ferguson5, Douglas Ferguson3, Steve Glossop1, Tyler Grebe3, Chungang Gu3, Sudhir Hande3, Janet Hawkins1, Alexander W Hird3, Jane Holmes1, James Horstick3, Yun Jiang6, Michelle L Lamb3, Thomas M McGuire1, Jane E Moore1, Nichole O'Connell5, Andy Pike1, Kurt G Pike1, Theresa Proia3, Bryan Roberts1, Maryann San Martin3, Ujjal Sarkar3, Wenlin Shao3, Darren Stead1, Neil Sumner1, Kumar Thakur3, Melissa M Vasbinder3, Jeffrey G Varnes3, Jianyan Wang2, Lei Wang6, Dedong Wu2, Liangwei Wu6, Bin Yang3, Tieguang Yao6.
Abstract
A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.Entities:
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Year: 2020 PMID： 33306391 DOI： 10.1021/acs.jmedchem.0c01754
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446