Optimization of 1-Methyl-3-(pyridin-3-yl)-1H-indol Derivatives as ROR1 Inhibitors with Improved Activity and
Qingquan Zheng1, Xingyang Qiu1, Dongdong Luo1
1Center for Molecular Oncology, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
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.
Insights
Researchers optimized LDR102, an indole-based compound, to create a highly selective small-molecule inhibitor targeting ROR1 (receptor tyrosine kinase-like orphan receptor 1). This new compound, 24d, shows potent antitumor activity and improved pharmacokinetic profiles for cancer therapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a key target in oncology due to its role in cancer malignancy.
- Existing ROR1-targeting biologics are in clinical trials, but selective small-molecule inhibitors are scarce.
- Previous work identified LDR102 as a novel ROR1 inhibitor but noted off-target kinase activity and suboptimal pharmacokinetics (PK).
Purpose of the Study:
- To address the limitations of LDR102, specifically its off-target effects and PK profile.
- To develop a novel, selective small-molecule inhibitor of ROR1 with enhanced therapeutic potential.
Main Methods:
- Systematic optimization of the LDR102 scaffold.
- Synthesis and evaluation of a series of 1-methyl-3-(pyridin-3-yl)-1H-indole derivatives.
- Assessment of ROR1 inhibitory potency, selectivity, in vitro/in vivo antitumor activity, and PK profiles.
Main Results:
- Discovery of compound 24d, a potent and selective ROR1 inhibitor.
- Compound 24d demonstrated robust antitumor efficacy in vitro and in vivo.
- Optimized PK profile for 24d was achieved, overcoming limitations of the parent compound.
Conclusions:
- Compound 24d represents a significant advancement in the development of selective ROR1 small-molecule inhibitors.
- The optimized derivative exhibits promising characteristics for further preclinical and clinical development in oncology.
- This study highlights the successful scaffold optimization strategy for developing targeted cancer therapeutics.
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