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.
Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
J Med Chem. 2024 Jul 11;67(13):10655-10686. doi: 10.1021/acs.jmedchem.4c00175. Epub 2024 Jun 24.
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 , 45 novel ROR1 inhibitors were designed and synthesized, and the detailed structure-activity relationship was investigated. Representative compound potently binds ROR1 with a value of 0.10 μM, exhibiting antitumor activity in lung cancer and breast cancer cell lines (IC: 0.36-1.37 μM). Additionally, a mechanism investigation demonstrated that compound induces the apoptosis of tumor cells. Importantly, compound significantly suppressed tumor growth in a mouse model without obvious toxicity. Overall, this work identified compound as a new ROR1 inhibitor, providing a novel lead compound for the treatment of lung cancer and breast cancer.
受体酪氨酸激酶样孤儿受体 1（ROR1）是几种恶性肿瘤中的致癌膜蛋白，已被认为是治疗人类癌症的有吸引力的靶点。在这项研究中，进行了基于结构的虚拟筛选和结构优化，以鉴定新型 ROR1 抑制剂。基于命中化合物，设计并合成了 45 种新型 ROR1 抑制剂，并研究了其详细的构效关系。代表性化合物 与 ROR1 的结合能力很强， 值为 0.10 μM，在肺癌和乳腺癌细胞系中具有抗肿瘤活性（IC：0.36-1.37 μM）。此外，机制研究表明化合物 诱导肿瘤细胞凋亡。重要的是，化合物 在没有明显毒性的情况下显著抑制了小鼠模型中的肿瘤生长。总体而言，这项工作鉴定了化合物 为一种新型的 ROR1 抑制剂，为治疗肺癌和乳腺癌提供了一种新的先导化合物。
