2. Academic Validation
  3. Discovery of 3,5-dimethylisoxazole derivatives as novel, potent inhibitors for bromodomain and extraterminal domain (BET) family

Discovery of 3,5-dimethylisoxazole derivatives as novel, potent inhibitors for bromodomain and extraterminal domain (BET) family

  • Bioorg Med Chem. 2021 Jun 1;39:116133. doi: 10.1016/j.bmc.2021.116133.
Lincheng Fang 1,  Zhaoxue Hu 1,  Yifei Yang 2,  Pan Chen 3,  Jinpei Zhou 4,  Huibin Zhang 5
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.
  • 5 Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zhanghb80@163.com.
PMID: 33862375 DOI: 10.1016/j.bmc.2021.116133
Abstract

Bromodomain and extra-terminal (BET) is a promising therapeutic target for various hematologic cancers. We used the BRD4 Inhibitor compound 13 as a lead compound to develop a variety of compounds, and we introduced diverse groups into the position of the compound 13 orienting toward the ZA channel. A series of compounds (14-23, 38-41, 43, 47-49) bearing triazolopyridazine motif exhibited remarkable BRD4 protein inhibitory activities. Among them, compound 39 inhibited BRD4(BD1) protein with an IC50 of 0.003 μM was superior to lead compound 13. Meanwhile, compound 39 possess activity, IC50 = 2.1 μM, in antiproliferation activity against U266 Cancer cells. On the other hand, compound 39 could arrest tumor cells into the G0/G1 phase and induce Apoptosis, which was consistent with its results in inhibiting cell proliferation. Biological and biochemical data suggest that BRD4 protein might be a therapeutic target and that compound 39 is an excellent lead compound for further development.

Keywords

BET inhibitors; Biological mechanism; Molecular docking; Multiple myeloma (MM).

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