Discovery of quinazoline derivatives CZw-124 as a pan-TRK inhibitor with potent anticancer effects in vitro and in vivo
- Eur J Med Chem. 2022 Aug 5:238:114451. doi: 10.1016/j.ejmech.2022.114451.
- 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
- 2. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: [email protected].
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%).