Discovery of novel phenyl triazole analogs as TRK/ALK dual inhibitors with prospective antitumor effects

• Published in: Bioorganic chemistry 2023-07, Vol.136, p.106563-106563, Article 106563
• Main Authors: Cao, Zhi, Zhang, Jiahao, Guo, Mengrao, Shao, Bin, Wei, Xiujian, Li, Sen, Wang, Peng, Zhai, Xin
• Format: Article
• Language: English
• Subjects: ALK; Anaplastic Lymphoma Kinase; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Cell Line, Tumor; Cell Proliferation; Dual inhibitor; Phenyl triazole; Prospective Studies; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Structure-Activity Relationship; Triazoles - pharmacology; TRK
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106563

[Display omitted] •A series of phenyl triazole analogs were designed as ALK/TRK dual inhibitors.•13a presented encouraging antiproliferative effects with apoptosis-inducing action.•13a suppressed migration and significantly inhibited KM12 cell colony formation.•The binding mode of 13a with ALK and TRKA ideally elucidated its excellent potency. 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 (ALKL1196M), 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.