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Alexander Drilon, MD

Gregory J. Riely, MD, PhD


Tropomyosin Receptor Kinases: A Potential Target for Tumors With NTRKM Gene Fusions

By: Joseph Fanelli
Posted: Thursday, September 15, 2022

According to findings presented in the European Journal of Medicinal Chemistry, the tropomyosin receptor kinase (TRK) TIY-7, designed by the study authors, has the potential to exert inhibitory activity against wild-type TRKA receptors and multiple-resistant TRKA and TRKC mutants when treating patients with cancer. Guang-Fu Yang, PhD, of Central China Normal University, Wuhan, and colleagues concluded that a conformational adjustment strategy of drug design may prove to be effective against resistant mutations.

“The new mode of action of our inhibitor may provide new and exciting insights into the discovery of second-generation TRK inhibitors to overcome multiple mutation-induced resistance,” they said.

In this study, the authors designed a new inhibitor combating multiple TRK mutants, including TRKA G595R, G667C, and F589L and TRKC G623R and G696A. They proposed a conformational adjustment strategy to prevent steric collision with the solvent front region.

Among the designed inhibitors, TIY-7 exhibited the best inhibitory activity against wild-type TRKA and mutant TRK proteins, including TRKA G595R, G667C, and F589L and TRKC G623R and G696A, according to the study authors. The inhibitor had inhibitory concentration (IC50) values of 2.9, 1.1, 0.7, 0.8, 0.8, and 0.2 nM, respectively. In addition, TIY-7 displayed satisfactory antitumor activity and inhibited tumor growth by 86% in a TRKC G623R xenograft model when administered orally at a dose of 30 mg/kg twice daily.

“These results prove that TIY-7 shows potential as an effective TRK inhibitor for wild-type and mutant NTRK fusion tumors, demonstrating the ability of our strategy to expedite the process to address multiple resistance mutations,” the authors concluded.

Disclosure: The authors reported no conflicts of interest.

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