Journal of Medicinal Chemistry p. 2180 - 2194 (2015)
Update date:2022-08-15
Topics:
Bruncko, Milan
Wang, Le
Sheppard, George S.
Phillips, Darren C.
Tahir, Stephen K.
Xue, John
Erickson, Scott
Fidanze, Steve
Fry, Elizabeth
Hasvold, Lisa
Jenkins, Gary J.
Jin, Sha
Judge, Russell A.
Kovar, Peter J.
Madar, David
Nimmer, Paul
Park, Chang
Petros, Andrew M.
Rosenberg, Saul H.
Smith, Morey L.
Song, Xiaohong
Sun, Chaohong
Tao, Zhi-Fu
Wang, Xilu
Xiao, Yu
Zhang, Haichao
Tse, Chris
Leverson, Joel D.
Elmore, Steven W.
Souers, Andrew J.
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.
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