2. Academic Validation
  3. Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors

Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors

  • J Med Chem. 2020 Feb 13;63(3):1337-1360. doi: 10.1021/acs.jmedchem.9b01721.
Yaxi Yang 1,  Rukang Zhang 2,  Zhaojun Li 3,  Lianghe Mei 4,  Shili Wan 1,  Hong Ding 2,  Zhifeng Chen 2,  Jing Xing 2,  Huijin Feng 1,  Jie Han 2,  Hualiang Jiang 2,  Mingyue Zheng 2 5,  Cheng Luo 2 5,  Bing Zhou 1 5 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China.
  • 2 Drug Discovery and Design Center, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China.
  • 3 School of Information Management , Dezhou University , No. 566 University Road West , Dezhou 253023 , Shandong , China.
  • 4 Suzhou Institute of Drug Innovation , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 108 Yuxin Road , Suzhou 213000 , Jiangsu , China.
  • 5 University of Chinese Academy of Sciences , 19 Yuquan Road , Beijing 100049 , China.
  • 6 Hangzhou Institute for Advanced Study , University of Chinese Academy of Sciences , Hangzhou 310024 , China.
PMID: 31910017 DOI: 10.1021/acs.jmedchem.9b01721
Abstract

p300 and CREB-binding protein (CBP) are ubiquitously expressed pleiotropic lysine acetyltransferases and play a key role as transcriptional co-activators that are essential for a multitude of cellular processes. Despite great importance, there is a lack of highly selective, potent, druglike p300/CBP inhibitors. Through the artificial-intelligence-assisted drug discovery pipeline and further optimization, we reported the discovery of novel, highly selective, potent small-molecule inhibitors of p300/CBP histone acetyltransferases (HAT) with desired druglike properties, exemplified by B026. Our data demonstrated that B026, with half maximal inhibitory concentration (IC50) values of 1.8 nM to p300 and 9.5 nM to CBP Enzyme inhibitory activity, is the most potent, selective p300/CBP HAT inhibitor. Moreover, B026 achieves significant and dose-dependent tumor growth inhibition in an animal model of human Cancer, suggesting that B026 is a highly promising p300/CBP HAT inhibitor and warrants extensive preclinical investigation as a potential clinical development candidate.

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