2. Academic Validation
  3. Discovery of quinazoline derivatives CZw-124 as a pan-TRK inhibitor with potent anticancer effects in vitro and in vivo

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.
Tianxiao Wu 1,  Qiaohua Qin 1,  Ruicheng Lv 1,  Nian Liu 1,  Wenbo Yin 1,  Chenzhou Hao 1,  Yin Sun 1,  Chu Zhang 1,  Yixiang Sun 1,  Dongmei Zhao 2,  Maosheng Cheng 1
Affiliations

Affiliations

  • 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: medchemzhao@163.com.
PMID: 35617855 DOI: 10.1016/j.ejmech.2022.114451
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%).

Keywords

Anticancer; NTRK gene Fusions; Pharmacodynamic; TRK inhibitors.

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