2. Academic Validation
  3. Design and development of a novel series of oral bivalent BET inhibitors with potent anticancer activities

Design and development of a novel series of oral bivalent BET inhibitors with potent anticancer activities

  • Eur J Med Chem. 2022 Sep 5;239:114519. doi: 10.1016/j.ejmech.2022.114519.
Menglan Luo 1,  Qian Wu 2,  Yueyue Yang 3,  Lin Sun 2,  Xiajuan Huan 2,  Changqing Tian 2,  Bing Xiong 3,  Zehong Miao 2,  Yingqing Wang 4,  Danqi Chen 5
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 2 State Key Laboratory of Drug Research,Cancer Research Center, 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.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China.
  • 4 State Key Laboratory of Drug Research,Cancer Research Center, 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: [email protected].
  • 5 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
PMID: 35714446 DOI: 10.1016/j.ejmech.2022.114519
Abstract

Bromodomain and extraterminal domain (BET) subfamily members are intriguing targets for Cancer treatment. Most of the reported BET inhibitors were monovalent inhibitors. Recently, some bivalent inhibitors were disclosed, which bound to two bromodomains simultaneously. They had good activities, however, most of them also showed unsatisfactory pharmacokinetic properties, which were caused by long chain linkers. Based on our previous work on monovalent BRD4 inhibitors, we designed and synthesized a series of novel bivalent inhibitors with short and hydrophilic linkers. These compounds exhibited better activities than the corresponding monovalent inhibitors and good pharmacokinetic properties. Compound 21 showed excellent in vitro activities. And it also demonstrated potent in vivo antitumor efficacy under oral administration and was well tolerated in in vivo tests.

Keywords

Anticancer; BET inhibitor; BRD4; Bivalent inhibitor.

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