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

化学 选择性 立体化学 组合化学 有机化学 催化作用
作者
Qingquan Zheng,Xingyang Qiu,Dongdong Luo,Hulin Ma,Yue Ming,Wenchen Pu,Min Ai,Jianhua He,Yong Peng
出处
期刊:Journal of Medicinal Chemistry [American Chemical Society]
卷期号:68 (11): 11188-11216 被引量:5
标识
DOI:10.1021/acs.jmedchem.5c00189
摘要

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, AblT315I, and PDGFRαV561D, 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.
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