Synthesis and Biological Evaluation of Diaminopyrimidine Derivatives as FAK Inhibitors With Anti‐glioblastoma Activity
TL;DR
Mechanistic studies demonstrated that both compounds could significantly induce cell cycle arrest of U118‐MG cells at the G2/M phase and effectively promote cancer cell apoptosis, and thereby block their unlimited proliferation.
Abstract
Glioblastoma (GBM) poses a severe threat to the health of the central nervous system. Among the existing therapeutic agents, the primary chemotherapeutic drug temozolomide is constrained by drug resistance. Thus, the development of new drugs for GBM treatment is urgently needed. Given that focal adhesion kinase (FAK) is highly associated with the occurrence and progression of GBM, this study conducted a scaffold hopping using TAE‐226 (The first approved FAK inhibitor and failed in phase II) as the parent nucleus to design and synthesize a series of diaminopyrimidine derivatives. Activity screening results showed that compounds 5f and 5o showed potent activity against U118‐MG cells with IC 50 values of 0.29 µM and 0.41 µM, as well as inhibited FAK kinase with IC 50 values of 10.23 and 11.87 nM, respectively. Further mechanistic studies demonstrated that both compounds could significantly induce cell cycle arrest of U118‐MG cells at the G2/M phase (7.84%–78.09%), effectively promote cancer cell apoptosis, and thereby block their unlimited proliferation. Molecular docking experiments further verified the mechanism underlying the high activity of these two compounds at the molecular level, providing an important structural basis and experimental evidence for the development of new molecules for GBM treatment.