Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

  • J Med Chem. 2017 May 11;60(9):3887-3901. doi: 10.1021/acs.jmedchem.7b00193.
Yujun Zhao  1 ,  Longchuan Bai  1 ,  Liu Liu  1 ,  Donna McEachern  1 ,  Jeanne A Stuckey  2 ,  Jennifer L Meagher  2 ,  Chao-Yie Yang  1 ,  Xu Ran  1 ,  Bing Zhou  1 ,  Yang Hu  1 ,  Xiaoqin Li  3 ,  Bo Wen  3 ,  Ting Zhao  3 ,  Siwei Li  3 ,  Duxin Sun  3 ,  Shaomeng Wang  1
Affiliations
  • 1. Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • 2. Life Sciences Institute and Department of Biological Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
PMID: 28463487 DOI: 10.1021/acs.jmedchem.7b00193
Abstract

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. Our data show that 31 is a potent, selective, and orally active BET inhibitor.

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