Optimization of 1-Methyl-3-(pyridin-3-yl)-1H-indol Derivatives as ROR1 Inhibitors with Improved Activity and Selectivity

ROR1 has garnered significant attention as a therapeutic target in oncology due to its critical involvement in cancer malignancy. Several biologics targeting ROR1 have advanced to clinical trials, but the development of selective small-molecule inhibitors remains limited. In our previous work, we identified the indole-based LDR102 as a novel ROR1 inhibitor with promising antitumor efficacy. However, subsequent studies revealed its off-target activity against kinases such as c-Kit, Abl^T315I, and PDGFRα^V561D, alongside suboptimal pharmacokinetic (PK) profiles. To address these limitations, we pursued a systematic optimization campaign focused on LDR102's scaffold. This effort produced a series of 1-methyl-3-(pyridin-3-yl)-1H-indole derivatives, culminating in the discovery of compound 24d. This lead candidate demonstrates exceptional ROR1 inhibitory potency, high selectivity, robust antitumor activity in vitro and in vivo, and an optimized PK profile, marking a substantive advance toward selective ROR1 inhibitors.