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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.
Luo et al. (Mon,) studied this question.