2. Academic Validation
  3. Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1

Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1

  • Biochem Pharmacol. 2021 Mar;185:114435. doi: 10.1016/j.bcp.2021.114435.
Qian Wu 1,  Dan-Qi Chen 2,  Lin Sun 1,  Xia-Juan Huan 3,  Xu-Bin Bao 3,  Chang-Qing Tian 1,  Jianping Hu 2,  Kai-Kai Lv 4,  Ying-Qing Wang 5,  Bing Xiong 6,  Ze-Hong Miao 7
Affiliations

Affiliations

  • 1 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 5 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China. Electronic address: yqwang@simm.ac.cn.
  • 6 University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China. Electronic address: bxiong@simm.ac.cn.
  • 7 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China. Electronic address: zhmiao@simm.ac.cn.
PMID: 33539817 DOI: 10.1016/j.bcp.2021.114435
Abstract

Bromodomain and extra-terminal domain (BET) family proteins are promising Anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak Anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the Anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing Apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the Anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new Anticancer mechanism.

Keywords

Anticancer activity; Bivalent BET inhibitors; Monovalent BET inhibitors; N2817; TAF1.

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