Discovery of Novel Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Inhibitors for Cancer Treatment
- J Med Chem. 2024 Jul 11;67(13):10655-10686. doi: 10.1021/acs.jmedchem.4c00175.
- 1. Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China.
- 2. Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is an oncogenic membrane protein in several malignancies and has been considered an attractive target for the treatment of human cancers. In this study, structure-based virtual screening and structure optimization were conducted to identify novel ROR1 inhibitors. Based on hit compound 2, 45 novel ROR1 inhibitors were designed and synthesized, and the detailed structure-activity relationship was investigated. Representative compound 19h potently binds ROR1 with a KD value of 0.10 μM, exhibiting antitumor activity in lung Cancer and breast Cancer cell lines (IC50: 0.36-1.37 μM). Additionally, a mechanism investigation demonstrated that compound 19h induces the Apoptosis of tumor cells. Importantly, compound 19h significantly suppressed tumor growth in a mouse model without obvious toxicity. Overall, this work identified compound 19h as a new ROR1 inhibitor, providing a novel lead compound for the treatment of lung Cancer and breast Cancer.