2. Academic Validation
  3. Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer

Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer

  • Bioorg Med Chem. 2024 Mar 1:101:117609. doi: 10.1016/j.bmc.2024.117609.
Jiuyu Liu 1,  Jingxuan Huang 1,  Kang Wang 1,  Yuan Li 1,  Chunting Li 1,  Yanli Zhu 1,  Xinzi He 1,  Yating Zhang 1,  Yanfang Zhao 1,  Changliang Hu 2,  Zhiguo Xi 2,  Minghui Tong 2,  Zhiwei Li 3,  Ping Gong 4,  Yunlei Hou 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.
  • 2 3D BioOptima, 1338 Wuzhong Avenue, Suzhou 215104, China.
  • 3 School of Medicine and Health, Yancheng Polytechnic College, 285 Jiefang South Road, Yancheng, Jiangsu 224005, China.
  • 4 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China. Electronic address: gongpinggp@126.com.
  • 5 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China. Electronic address: houyunlei901202@163.com.
PMID: 38364599 DOI: 10.1016/j.bmc.2024.117609
Abstract

In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50 = 17.3 nM, MDA-MB-361 IC50 = 8.4 nM, and MV4-11 IC50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-t = 657 ng·h·mL-1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and Apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel Anticancer agents as dual inhibitors of PLK1 and BRD4.

Keywords

Anticancer activity; Dihydropteridone derivatives; Isoindolin-1-one or isoindoline moieties; PLK1/BRD4 dual inhibitors; Structure activity relationship.

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