The exploration of novel anaplastic lymphoma kinase (ALK) and tropomyosin receptor kinase (TRK) dual inhibitors tended to serve as targeted treatment of cancer. Herein, a series of phenyl triazole derivatives were designed and synthesized as ALK/TRK dual regulators based on structure-based drug design (SBDD) strategy and were evaluated for antiproliferative activity by MTT assay. Accordingly, all compounds showed surprising cytotoxicity with IC₅₀ values below 10 μM on KM12, H2228 and KARPAS299 cell lines. Among them, compound 13a bearing (2-(4-methylpiperazin-1-yl)phenyl)morpholinomethanone moiety was identified as the optimal hit in enzymatic screening with IC₅₀ values of 1.9 nM (TRKA), 7.2 nM (ALK) and 65.2 nM (ALK^L1196M), respectively. Furthermore, 13a could inhibit KM12 cell migration and colony formation in a dose dependent manner. Meanwhile, AO/EB staining indicated that the pro-apoptotic effect of 13a was comparable to that of Entrectinib at the dose of 200 nM. Ultimately, the binding model of 13a with TRKA and ALK well established its mode of action which accounted for the superior activities as a promising antitumor candidate.

新型间变性淋巴瘤激酶（ALK）和原肌球蛋白受体激酶（TRK）双重抑制剂的探索倾向于作为癌症的靶向治疗。在此，基于基于结构的药物设计（SBDD）策略设计合成了一系列苯基三唑衍生物作为 ALK/TRK 双调节剂，并通过 MTT 法评估了其抗增殖活性。因此，所有化合物在 KM12、H2228 和 KARPAS299 细胞系上均显示出令人惊讶的细胞毒性，IC _{50值低于 10 μM。}其中，带有 (2-(4-methylpiperazin-1-yl)phenyl)morpholinomethanone moiety 的化合物13a在酶促筛选中被鉴定为最佳命中，IC 50 值为 1.9 _nM (TRKA)、7.2 nM (ALK) 和 65.2 nM (ALK ^L1196M）， 分别。此外，13a可以剂量依赖性方式抑制 KM12 细胞迁移和集落形成。同时，AO/EB 染色显示13a的促凋亡作用与 200 nM 剂量的 Entrectinib 相当。最终， 13a与 TRKA 和 ALK 的结合模型很好地确立了其作用模式，这解释了作为有前途的抗肿瘤候选物的卓越活性。