Discovery of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives as potent anticancer agents via ROR1 inhibition

[Display omitted] •A series of novel 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives were designed and synthesized.•7h exhibited the most pronounced anti-proliferative activity, with IC50 value of 3.5 μM against H1975 cells.•7h possessed a favorable safety profile with a selectivity index (SI) of 22.9 between H1975 cells and MRC-5 cells.•7h exhibited notable inhibitory effects on the proliferation, migration, and invasion of H1975 cells as a small molecule ROR1 inhibitor.•7h significantly attenuated H1975 cell growth through G1 phase arrests and showed favorable PK profiles in vivo. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the receptor tyrosine kinase family, which was overexpressed in non-small cell lung cancer (NSCLC) and essential for cell proliferation, migration and invasion. Recently, accumulating evidences indicated that ROR1 played a critical role in maintaining the balance between the Src survival pathway and the p38 apoptotic pathway. Hence, ROR1 was considered as an attractive therapeutic target for the development of anticancer drugs. However, only a few small molecule ROR1 inhibitors were reported until now. Herein, a series of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives were designed and synthesized via bioisosterism and simplification strategy guided by the lead compound 9a. MTT assay showed that compound 7h exhibited the best anti-cancer properties with IC50 values of 18.16, 8.11 and 3.5 μM against A549, PC9 and H1975 cells, respectively. Meanwhile, the selectivity index (SI) of compound 7h for H1975 cells was 22.86 compared to that of the lead compound 9a of 1.83, which is at least 12 fold higher than that of lead compound 9a, suggesting that 7h had a favorable safety profile. In addition, the molecular docking, CETSA and DARTS assays suggested that compound 7h might be a novel small molecule ROR1 inhibitor. More importantly, compound 7h significantly suppressed the migration and invasion of H1975 cells in vitro by blocking Src survival pathway and reactivating the p38 apoptotic pathway, and induced H1975 cell cycle arrest in G1 phase. Collectively, our work suggested that the ROR1 inhibitor 7h might be a novel drug candidate for NSCLC treatment.