Document Report Card

ID: ALA3414447

Journal: J Med Chem

Title: Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.

Authors: Bruncko M, Wang L, Sheppard GS, Phillips DC, Tahir SK, Xue J, Erickson S, Fidanze S, Fry E, Hasvold L, Jenkins GJ, Jin S, Judge RA, Kovar PJ, Madar D, Nimmer P, Park C, Petros AM, Rosenberg SH, Smith ML, Song X, Sun C, Tao ZF, Wang X, Xiao Y, Zhang H, Tse C, Leverson JD, Elmore SW, Souers AJ.

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.

CiteXplore: 25679114

DOI: 10.1021/jm501258m