用于癌症免疫治疗新型RORγt激动剂的设计合成与作用机制研究

Cancer immunotherapy has become one of the most important cancer treatments with PD-1/PD-L1 antibody drugs going to the market. Modulating immune system with small molecule agents could offer complementary advantages to antibodies, such as lower cost, oral-availability and higher exposure in tumor tissues, thus becoming one of the most attractive research fields for both academic institutes and pharmaceutical companies. Retinoic acid receptor-related orphan receptor-gamma-t (RORγt) regulates Th17 cell differentiation and IL-17A production, which has potential to exercise antitumor efficacy by eliciting remarkable activation of CD8+ T cells. Therefore, development of RORγt agonists could provide a unique approach for cancer immunotherapy. Previously, we identified a tertiary amine RORγt agonist and its co-crystal structure with RORγt LBD was resolved. In this proposal, we dock the early discovered biaryl and carbazole RORγt inhibitors to the tertiary amine RORγt agonist co-crystal structure, identify the key structural elements to realize the inhibitor to agonist switch, and design the novel series of RORγt agonists. The RORγt activity and developability profile of the new series will be optimized for cancer immunotherapy drug candidate selection. At the same time, the binding mode and MOA of the newly discovered RORγt agonist will be fully explored.

癌症免疫疗法随着PD-1/PD-L1单抗药物的上市已成为癌症治疗的焦点。癌症免疫治疗小分子药物由于其生产成本低、使用方便、在肿瘤组织中能达到更高暴露量等优势，也已成为近年来学术界和药企的研发热点。RORγt是癌症免疫治疗小分子药物研发的新靶点。RORγt激动剂能够促进Th17细胞分化和IL-17A的产生，激活肿瘤特异性CD8+T细胞，发挥癌症免疫作用。本项目以前期发现的联芳基类RORγt抑制剂和咔唑类RORγt抑制剂为先导化合物，根据叔胺与RORγt LBD复合物晶体结构，通过分子对接技术分析配体与受体间的相互作用，寻找将抑制剂转变为激动剂的关键要素和结构位点，应用骨架拼合和生物电子等排原理，设计合成新型RORγt激动剂并对其活性及成药性进行优化，以期获得具有自主知识产权、安全有效的癌症免疫治疗小分子候选药物。同时，对新发现的RORγt激动剂与受体的结合模式和作用机制做进一步深入研究。

孤儿核受体RORγt是肿瘤免疫治疗小分子药物研发的新靶点。RORγt激动剂近年来已成为抗肿瘤新药研发的热点领域。RORγt激动剂能够促进Th17细胞分化和IL-17A的产生，激活肿瘤特异性CD8+T细胞，发挥癌症免疫治疗作用。本项目以前期发现的叔胺类RORγt激动剂、联芳基类RORγt抑制剂和咔唑类RORγt抑制剂为先导化合物，基于复合物晶体结构，利用计算机模拟技术，结合骨架跃迁和生物电子等排原理，设计合成叔胺类、联芳基类、咔唑类和吲哚啉类4个RORγt激动剂化合物系列，经多轮活性及成药性优化获得1个联芳基类RORγt激动剂候选药物YW-YH-7-069，其受体和细胞活性好、口服生物利用度高、具有与临床化合物LYC-55716（phase II，Lycera公司）相当或更高的抗肿瘤药效并且毒性小、安全性高。目前已申请和授权多项中国专利和国际专利，具有广阔的临床开发和转化前景。本项目还通过对咔唑酰胺类RORγt激动剂和反向激动剂的复合物晶体结构解析，探讨了咔唑6位取代基大小对维持活性功能域AF2稳定和激活基因转录的影响。进一步的分子动力学模拟研究揭示了激动剂、“长”、“短”反向激动剂引起LBD 结构域构象变化的规律和分子机制，为RORγt激动剂和反向激动剂的优化设计提供指导。