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  3. Design, synthesis and anticancer activity evaluation of 4-(3-1H-indazolyl)amino quinazoline derivatives as PAK4 inhibitors

Design, synthesis and anticancer activity evaluation of 4-(3-1H-indazolyl)amino quinazoline derivatives as PAK4 inhibitors

  • Bioorg Med Chem. 2023 Nov 15:95:117501. doi: 10.1016/j.bmc.2023.117501.
Wei Han 1,  Yusang Yang 1,  Fan Yu 2,  Qianqian Li 1,  Anyao Liu 1,  Wenbo Xu 1,  Jiabin Li 3,  Xiaowen Xue 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2 The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing 211198, China.
  • 3 School of Science, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
PMID: 37864885 DOI: 10.1016/j.bmc.2023.117501
Abstract

A novel series of 4-(3-1H-indazolyl)amino quinazoline derivatives were developed as PAK4 inhibitors based on a scaffold hopping strategy. Compounds 27e, 27g, 27i and 27j were found to exhibit potent inhibitory activity against PAK4 (IC50 = 10, 13, 11 and 9 nM, respectively). Subsequent cellular assay demonstrated that compound 27e possessed the strongest antiproliferative activity against A549 cells with an IC50 value of 0.61 μM, a little bit better than PF-3758309. Further Anticancer mechanistic investigation revealed that compound 27e significantly induced Apoptosis of A549 cells in a concentration-dependent manner and blocked the cell cycle at phase G0/G1. A docking model between compound 27e and PAK4 was proposed to elucidate its possible binding modes. As a promising PAK4 Inhibitor, compound 27e may serve as a candidate for the development of novel PAK4-targeted Anticancer drug.

Keywords

4-(3-1H-indazolyl)amino quinazoline derivatives; Anti-cancer; Apoptosis; Cell cycle arrest; PAK4 inhibitors.

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