Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Minhang Hi-tech Zone, Shanghai 200245, China.
Eternity Bioscience Inc., 6 Cedarbrook Drive, Cranbury, New Jersey 08512, United States.
J Med Chem. 2021 Oct 28;64(20):14983-14996. doi: 10.1021/acs.jmedchem.1c00828. Epub 2021 Oct 13.
RORγ is a dual-functional drug target, which involves not only induction of inflammation but also promotion of cancer immunity. The development of agonists of RORγ promoting Th17 cell differentiation could provide a novel mechanism of action (MOA) as an immune-activating anticancer agent. Herein, we describe new 2-(ortho-substituted benzyl)-indole derivatives as RORγ agonists by scaffold hopping based on clinical RORγ antagonist VTP-43742. Interestingly, subtle structural differences of the compounds led to the opposite biological MOA. After rational optimization for structure-activity relationship and pharmacokinetic profile, we identified a potent RORγ agonist compound that was able to induce the production of IL-17 and IFNγ in tumor tissues and elicit antitumor efficacy in MC38 syngeneic mouse colorectal tumor model. This is the first comprehensive work to demonstrate the antitumor efficacy of an RORγ agonist.
RORγ 是一个具有双重功能的药物靶点，不仅涉及炎症的诱导，还涉及癌症免疫的促进。开发促进 Th17 细胞分化的 RORγ 激动剂可以为免疫激活抗癌药物提供一种新的作用机制 (MOA)。在此，我们通过基于临床 RORγ 拮抗剂 VTP-43742 的支架跳跃，将新型 2-(邻位取代苄基)-吲哚衍生物描述为 RORγ 激动剂。有趣的是，化合物的细微结构差异导致了相反的生物学 MOA。在对结构-活性关系和药代动力学特征进行合理优化后，我们鉴定出一种有效的 RORγ 激动剂化合物 ，该化合物能够在肿瘤组织中诱导 IL-17 和 IFNγ 的产生，并在 MC38 同源小鼠结直肠肿瘤模型中发挥抗肿瘤功效。这是首次全面证明 RORγ 激动剂具有抗肿瘤功效的工作。
