Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 12, Pages 4927-4939Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00613
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Funding
- National Institutes of Health [P50 CA186786, P30 CA046592]
- Prostate Cancer Foundation
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor grant [085P1000817]
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Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of gamma-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with K-i values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 angstrom resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.
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