Optimization of 1‑Methyl-3-(pyridin-3-yl)‑1<i>H</i>‑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 <b>LDR102</b> 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 <b>LDR102</b>’s scaffold. This effort produced a series of 1-methyl-3-(pyridin-3-yl)-1<i>H</i>-indole derivatives, culminating in the discovery of compound <b>24d</b>. This lead candidate demonstrates exceptional ROR1 inhibitory potency, high selectivity, robust antitumor activity <i>in vitro</i> and <i>in vivo</i>, and an optimized PK profile, marking a substantive advance toward selective ROR1 inhibitors.