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

Wei Han; Yusang Yang; Fan Yu; Qianqian Li; Anyao Liu; Wenbo Xu; Jiabin Li; Xiaowen Xue

doi:10.1016/j.bmc.2023.117501

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. Epub 2023 Oct 13.

Authors

Wei Han¹, Yusang Yang¹, Fan Yu², Qianqian Li¹, Anyao Liu¹, Wenbo Xu¹, Jiabin Li³, Xiaowen Xue⁴

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.

Trial registration: ClinicalTrials.gov NCT02702492.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry
Quinazolines* / chemistry
Structure-Activity Relationship

Substances

Quinazolines
Protein Kinase Inhibitors
Antineoplastic Agents

Associated data

ClinicalTrials.gov/NCT02702492