| Literature DB >> 25679114 |
Milan Bruncko1, Le Wang, George S Sheppard, Darren C Phillips, Stephen K Tahir, John Xue, Scott Erickson, Steve Fidanze, Elizabeth Fry, Lisa Hasvold, Gary J Jenkins, Sha Jin, Russell A Judge, Peter J Kovar, David Madar, Paul Nimmer, Chang Park, Andrew M Petros, Saul H Rosenberg, Morey L Smith, Xiaohong Song, Chaohong Sun, Zhi-Fu Tao, Xilu Wang, Yu Xiao, Haichao Zhang, Chris Tse, Joel D Leverson, Steven W Elmore, Andrew J Souers.
Abstract
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.Entities:
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Year: 2015 PMID： 25679114 DOI： 10.1021/jm501258m
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446