Design, synthesis and anti-tumor efficacy of novel phenyl thiazole/triazole derivatives as selective TrkA inhibitors. (15th October 2022)

• Record Type: Journal Article
• Authors: Wang, Xinyu; Tan, Zehui; Wang, Fuyi; Zhang, Jiahao; Yang, Juanjuan; Liu, Shuyu; Jiang, Nan; Zhai, Xin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 72(2022)
• Publication Date: 2022-10-15
• Subjects: TrkA -- Phenyl thiazole/triazole -- Kinase inhibitor -- Antitumor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116995
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Novel phenyl thiazole/triazole derivatives were designed and synthesized. 19c showed excellent inhibitory potency and selectivity on TrkA (IC50 = 1.6 nM). The binding mode of 19c with TrkA ideally elucidated its excellent enzymatic potency. 19c suppressed migration and significantly inhibited KM-12 cell colony formation. 19c weakly induced apoptosis of KM-12 cell in immunofluorescent staining analysis. Abstract: Aiming to develop novel tropomyosin receptor kinase A (TrkA) inhibitors, a scaffold hopping strategy was utilized by transforming the fused indazole of Entrectinib to phenyl triazole/thiazole skeleton to obtain compounds 7a -7 h and 13a -13 h . In the light of MTT assay, phenyl triazole derivatives 7a-7 h exhibited moderate anti-proliferative activities against KM-12 cells with the IC50 values of 1.78–17.51 μM, while phenyl thiazole derivatives 13a-13 h showed the weaker efficacy. Further structure-guided optimizations by combining the phenyl triazole skeleton with 3, 5‑difluorophenyl and 3-carbamoyl-4-piperazinylaniline moiety led to compounds 19a -19d and 20 . Eventually, 19c bearing (2-(4-methylpiperazin-1-yl)phenyl)(morpholino)methanone moiety exhibited excellent anti-proliferative activity on TrkA-positive KM-12 cells with IC50 value of 0.17 μM. Meanwhile, compound 19c showed the inhibitory potency on TrkA with IC50 value of 1.6 nM, and displayed higher selectivity on TrkA over TrkB (IC50 = 12.3 nM) and TrkC (IC50 = 18.4 nM). The dedicated wound healing and colony formation assay indicated that the optimal compound 19c could suppress migration and significantly inhibit KM-12 cell colony formation in a dose-dependent manner. In addition, 19c could weakly induce apoptosis of KM-12 cell in immunofluorescent staining analysis. Taken together, the above results suggest 19c as a novel TrkA inhibitor worthy of further profiling.