Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors

The HGF/Met signaling pathway is over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed high antiproliferative activities in c-Met sensitive tumor cell lines (PC-3, Panc-1, HepG2, HCT116 and Caki-1) with IC50 values from 0.53 to 1.37 mu M. The lead compound 34a displayed outstanding c-Met inhibitory activity ( IC50: 15.0 nM) and antiproliferative activities. Furthermore, 34a also performed favorable pharmacokinetic properties in mice (F%: 59.3) and an acceptable safety profile in preclinical studies. Further docking studies showed a common interaction of 34a with c-Met at the ATP-binding site, which indicated that 34a could be a potential candidate for c-Met inhibitors. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

In this study, novel N-phenylpyrimidin-2-amine derivatives were developed and many compounds were found to inhibit c-Met kinase, showing high antiproliferative activities in c-Met sensitive tumor cell lines. Compound 34a showed outstanding inhibitory activity and pharmacokinetic properties, making it a potential candidate for c-Met inhibitors.