Design, synthesis, and biological evaluation of novel covalent inhibitors targeting focal adhesion kinase

Tao Chen; Yan Liu; Mingsong Shi; Minghai Tang; Wenting Si; Xue Yuan; Yi Wen; Lijuan Chen

doi:10.1016/j.bmcl.2021.128433

Design, synthesis, and biological evaluation of novel covalent inhibitors targeting focal adhesion kinase

Bioorg Med Chem Lett. 2021 Dec 15:54:128433. doi: 10.1016/j.bmcl.2021.128433. Epub 2021 Oct 30.

Authors

Tao Chen¹, Yan Liu¹, Mingsong Shi¹, Minghai Tang¹, Wenting Si¹, Xue Yuan¹, Yi Wen¹, Lijuan Chen²

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China.
² State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China. Electronic address: chenlijuan125@163.com.

PMID: 34757216
DOI: 10.1016/j.bmcl.2021.128433

Abstract

Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC₅₀ value of 35 nM and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC₅₀ values of 0.41, 0.01 and 0.11 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G₂/M phase, inducing tumor cell apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK.

Keywords: Apoptosis; Cancer; Cell proliferation; Covalent inhibitor; FAK.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Focal Adhesion Kinase 1 / antagonists & inhibitors*
Focal Adhesion Kinase 1 / metabolism
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Focal Adhesion Kinase 1
PTK2 protein, human