Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9 H -pyrimido[4,5- b ]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor
- Univ. of Michigan, Ann Arbor, MI (United States); Chinese Academy of Sciences, Shanghai (China)
- Univ. of Michigan, Ann Arbor, MI (United States)
- Univ. of Michigan, Ann Arbor, MI (United States); Univ. of California, San Francisco, CA (United States)
We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Here, our data show that 31 is a potent, selective, and orally active BET inhibitor.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC); National Inst. of Health; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor
- Grant/Contract Number:
- AC02-06CH11357; P30CA046592; P50 CA186786; 085P1000817
- OSTI ID:
- 1373777
- Journal Information:
- Journal of Medicinal Chemistry, Vol. 60, Issue 9; ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Synthesis of Isoquinolines through Ir III -Catalyzed C-H Activation/Annulation from Benzimidates with Hydroxylisopropylalkynes: Synthesis of Isoquinolines through Ir III -Catalyzed C-H Activation/Annulation from Benzimidates with Hydroxylisopropylalkynes
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journal | June 2018 |
Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3β Inhibitors
|
journal | June 2019 |
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