2. Academic Validation
  3. Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers

Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers

  • J Med Chem. 2025 Jan 23;68(2):1344-1364. doi: 10.1021/acs.jmedchem.4c01933.
Kaikai Lyu 1 2,  Ying Ren 3,  Jie Mou 3,  Yunfang Yang 3,  Yaoyao Pan 3,  Huijie Zhang 1 2,  Yanlian Li 1,  Danyan Cao 1,  Lin Chen 1,  Danqi Chen 1 2,  Dong Guo 3,  Bing Xiong 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 Jiangsu Key Laboratory of New Drug and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221006, China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
PMID: 39844725 DOI: 10.1021/acs.jmedchem.4c01933
Abstract

Simultaneous inhibition of the bromodomain and extra-terminal domain and Aurora kinases is a promising Anticancer therapeutic strategy. Based on our previous study on BET-kinase dual inhibitors, we employed the molecular docking approach to design novel dual BET-Aurora kinase A inhibitors. Through several rounds of optimization and with the guidance of the solved cocrystal structure of BRD4 bound to inhibitor 27, we finally obtained a series of highly potent dual BET-Aurora kinase A inhibitors. Compound 38 exhibited strong affinity toward both BRD4 and Aurora Kinase A. It also showed good antiproliferative activities on diverse Cancer cell lines, good pharmacokinetic profiles, and favorable antitumor efficacy in renal cell Cancer and colon Cancer xenograft models with TGI of 45.99% and 53.06%, respectively. The development of compound 38 reinforces the concept that a rational design may achieve dual inhibitors targeting specific kinases and bromodomain proteins.

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