Design, synthesis and biological evaluation of ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors

Hongming Xie; Xinglong Lin; Yingjun Zhang; Fuxing Tan; Bo Chi; Zhihong Peng; Wanrong Dong; Delie An

doi:10.1016/j.bmcl.2020.127459

Design, synthesis and biological evaluation of ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127459. doi: 10.1016/j.bmcl.2020.127459. Epub 2020 Aug 9.

Authors

Hongming Xie¹, Xinglong Lin², Yingjun Zhang³, Fuxing Tan², Bo Chi², Zhihong Peng⁴, Wanrong Dong¹, Delie An⁵

Affiliations

¹ State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China.
² The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd, Dongguan 523871, PR China.
³ The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd, Dongguan 523871, PR China. Electronic address: ZhangYingjun@hec.cn.
⁴ State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China. Electronic address: pzh7251@hnu.edu.cn.
⁵ State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China. Electronic address: deliean@hnu.edu.cn.

PMID: 32784087
DOI: 10.1016/j.bmcl.2020.127459

Abstract

We report herein the synthesis of novel ring-fused pyrazoloamino pyridine/pyrimidine derivatives as potential FAK inhibitors and the evaluation of pharmaceutical activity against five cancer cell lines (MDA-MB-231, BXPC-3, NCI-H1975, DU145 and 786O). Generally, the majority of compounds displayed strong anti-FAK enzymatic potencies (IC₅₀ < 1 nM) and could effectively inhibit several class of cancer cell lines within the concentration of 3 μM in comparison with GSK2256098 as a reference. Among them, compound 4o is considered to be the most effective due to high sensitivity in antiproliferation. In culture, 4o could not only inhibit FAK Y397 phosphorylation in MDA-MB-231 cell line, but also trigger apoptosis in a dose-dependent manner. Furthermore, computational docking analysis also suggested that 4o and TAE-226 displayed the similar interaction with FAK kinase domain.

Keywords: Anticancer activity; FAK; Inhibitor; Pyrimidine/pyridine; Ring-fused pyrazoloamino.

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
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*
Pyridines / chemistry
Pyridines / pharmacology*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

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