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.

原肌球蛋白受体激酶 (TRK) 是 TRKA、TRKB 和 TRKC 同种型的一个家族。据广泛报道，TRK 与多种肿瘤有关，目前临床治疗中使用或评估了几种Pan -TRK 抑制剂。然而， Pan -TRK抑制剂在临床使用中经常发生脱靶不良事件，导致患者依从性差，甚至停药。尽管亚型选择性 TRK 抑制剂可以避免潜在的脱靶不良事件，并且可以作为 TRK 生化研究中更强大的工具化合物，但 TRK 的高度序列相似性阻碍了亚型选择性 TRK 抑制剂的开发。例如，没有报道过选择性TRKC抑制剂。在此，选择性 TRKC 抑制剂（L13 ) 被公开，具有有效的 TRKC 抑制活性和比 TRKA/B 高 107.5-/34.9 倍的选择性（IC ₅₀ TRKA/B/C = 1400 nM、454 nM、13 nM，分别）。广泛的分子动力学模拟表明，L13与不同 TRK 的核糖区域中的残基和不同保守的水分子的关键相互作用可能是选择性的结构基础。这将为亚型选择性 TRK 抑制剂的开发提供启发性的见解。此外，L13可以作为一种工具化合物来研究 TRKC 的独特生物学功能，并作为进一步研究专门针对 TRKC 的药物的起点。