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J Med Chem. 2015 Mar 12;58(5):2180-94. doi: 10.1021/jm501258m. Epub 2015 Feb 26.

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

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AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.


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.

[Indexed for MEDLINE]

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