Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor.

European journal of medicinal chemistry 2022 Nov 05

filter terms:

Tropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a more powerful tool compound in the biochemical studies on TRKs, the high sequence similarities of TRKs hinder the development of subtype-selectivity TRK inhibitors. For example, no selective TRKC inhibitor has been reported. Herein, a selective TRKC inhibitor (L13) was disclosed, with potent TRKC inhibitory activity and 107.5-/34.9-fold selectivity over TRKA/B (IC50 TRKA/B/C = 1400 nM, 454 nM, 13 nM, respectively). Extensive molecular dynamics simulations illustrated that key interactions of L13 with the residues and diversely conserved water molecules in the ribose regions of different TRKs may be the structural basis of selectivity. This will provide inspiring insights into the development of subtype-selectivity TRK inhibitors. Moreover, L13 could serve as a tool compound to investigate the distinct biological functions of TRKC and a starting point for further research on drugs specifically targeting TRKC. Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Citation

Zhijie Wang, Jiwei Ren, Kun Jia, Yuming Zhao, Li Liang, Zitian Cheng, Fei Huang, Xiaofei Zhao, Jie Cheng, Shiyu Song, Tiancheng Sheng, Weiqi Wan, Qingqing Shu, Donglin Wu, Junhao Zhang, Tao Lu, Yadong Chen, Ting Ran, Shuai Lu. Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor. European journal of medicinal chemistry. 2022 Nov 05;241:114601