Document Report Card
Basic Information
ID: ALA5137027
Journal: Eur J Med Chem
Title: Discovery of quinazoline derivatives CZw-124 as a pan-TRK inhibitor with potent anticancer effects in vitro and in vivo.
Authors: Wu T, Qin Q, Lv R, Liu N, Yin W, Hao C, Sun Y, Zhang C, Sun Y, Zhao D, Cheng M.
Abstract: Herein, we report the discovery process and antitumor activity of the TRK inhibitor CZw-124 (8o), which is a quinazoline derivative. Starting from a PAK4 inhibitor, we used various drug design strategies, including pharmacophore feature supplementation, F-scanning, and blocking metabolic sites, and finally found a TRK inhibitor CZw-124 that is effective in vitro and in vivo. Docking studies and molecular dynamics simulations revealed a possible mode of binding of CZw-124 to TRKA. Biological activity evaluation showed that CZw-124 belongs to a class of pan-TRK inhibitors with moderate kinase selectivity. It inhibited the proliferation and induced the apoptosis of Km-12 cells in vitro by interfering with the phosphorylation of TRKA. Pharmacodynamic evaluation in vivo showed that CZw-124 had a tumor inhibition rate comparable to that of larotrectinib after oral administration of 40 mg/kg/d (tumor growth inhibiton = 71%).
CiteXplore: 35617855