Phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with enhanced activity against pancreatic cancer cell lines

He Liu; Bin Wu; Yang Ge; Jiaxin Huang; Shijie Song; Changyuan Wang; Jihong Yao; Kexin Liu; Yanxia Li; Yongming Li; Xiaodong Ma

doi:10.1016/j.bmc.2017.09.041

Phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with enhanced activity against pancreatic cancer cell lines

Bioorg Med Chem. 2017 Dec 15;25(24):6313-6321. doi: 10.1016/j.bmc.2017.09.041. Epub 2017 Sep 30.

Authors

He Liu¹, Bin Wu¹, Yang Ge¹, Jiaxin Huang¹, Shijie Song¹, Changyuan Wang¹, Jihong Yao¹, Kexin Liu¹, Yanxia Li², Yongming Li³, Xiaodong Ma⁴

Affiliations

¹ College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, PR China.
² Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
³ College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, PR China. Electronic address: liyongming1979@sina.com.
⁴ College of Pharmacy, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.

PMID: 29102081
DOI: 10.1016/j.bmc.2017.09.041

Abstract

A family of phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) were synthesized as potent focal adhesion kinase (FAK) inhibitors. The PA-DPPY derivatives could significantly inhibit the FAK enzymatic activity at concentrations lower than 10.69 nM. Among them, compounds 7a and 7e were two of the most active FAK inhibitors, possessing IC₅₀ values of 4.25 nM and 4.65 nM, respectively. In particular, compound 7e also displayed strong activity against AsPC cell line, with an IC₅₀ of 1.66 μM, but show low activity against the normal HPDE6-C7 cells (IC₅₀ > 20 μM), indicating its low cell cytotoxicity. Additionally, flow cytometry analysis showed that after treatment with 7e (8 μM, 72 h), both AsPC and Panc cells growth were almost totally inhibited, with a cell viability rate of 16.8% and 18.1%, respectively. Overall, compound 7e may be served as a valuable FAK inhibitor for the treatment of pancreatic cancer.

Keywords: FAK; Inhibitor; Pancreatic cancer; Pyrimidine.

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
Dimethoate / chemistry
Dimethoate / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Focal Adhesion Kinase 1 / antagonists & inhibitors*
Focal Adhesion Kinase 1 / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

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