A new type of primary myoprotein-like subject kinase inhibitor has been developed

recently, Liu Qingsong and Liu Jing Pharmaceuticals, researchers at the Institute of Health and Medical Technology of the
Hefei Institute of Physical Sciences in China, developed a new type of primary muscle
-subject kinase (TRK) small molecule inhibitor IHMT-TRK-284. The results were published online in the International Journal of Pharmaceutical Chemistry, European Journal of Medicinal Chemistry.
TRK mainly consists of TRKA, TRKB and TRKC subsypes, which are encoded by the NTRK1, NTRK2 and NTRK3 genes respectively. When chromosomal variation occurs after NTRK gene fusion, TRK kinase is phosphatized and activates downstream signaling path, thus regulating cell growth, differentiation, invasion, migration, apoptosis, etc. The NTRK gene fusion occurs in a variety of solid tumors in adults and children, including breast cancer, colorectal cancer, non-small cell lung cancer, and a variety of sarcomas. NTRK gene fusion occurs in 1-3% of patients with non-small cell lung cancer and colorectal cancer, and in rare cancers, such as infant fibroblastoma and breast secretion cancer, up to 90% of patients have NTRK gene fusion. As a result, TRK is considered a broad-spectrum target for cancer treatment, and the development of TRK kinase inhibitors has received attention in the field of pharmacy.
researchers in the previous study, based on the team-built BaF3 engineering cell bank, through high-volume screening found that the compound CHFML-ABL-121 for TRKA/B/C has a strong inhibitory effect, but the compound at the same time on a variety of kinase targets have inhibitory effect, and the drug is poor. Therefore, based on the design concept of type II kinase inhibitors, the researchers developed a new TRK kinase inhibitor, IHMT-TRK-284, which is highly selective and can overcome a variety of drug-resistant mutations, through drug-effect fragment combinations. The compound showed strong inhibition of TRKA, TRKB and TRKC kinases as well as clinically resistant mutations at the protein and cellular levels. Further in vivo studies showed that IHMT-TRK-284 showed good pharmacodynamic properties in different genus, and showed dose-dependent anti-tumor effects on mouse transplant tumor models of km-12-LUC and other cells. The compound is currently undergoing a comprehensive preclinical drug evaluation.
the research has been supported by the National Natural Science Foundation of China,
"personalized drugs" pilot special, "major new drug creation" national science and technology major special projects. (Source: Hefei Institute of Material Sciences, Chinese Academy of sciences)
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