新型亚型选择性CARM1抑制剂的合理设计、合成及抗肿瘤活性研究

Protein arginine methyltransferase CARM1 plays an important role in the development of cancer and has become a new target for cancer treatment. The development of isoform-selective CARM1 inhibitors is of great significance for targeted therapy of cancer. In previous study, we have found a novel small molecule inhibitor of CARM1 with isoform-selectivity and antitumor activity, which binds to the substrate-binding site of CARM1 particularly with interactions with a known selective pocket. Further analysis of protein structure revealed that there is another potential selective pocket at the substrate-binding site. Therefore, this project proposes to use the new pocket for the rational design of the small molecule inhibitor discovered in previous study, so that it can act on both new and old selective pockets simultaneously with improved isoform-selectivity. Then the designed compounds will be biologically evaluated in vitro and in vivo and studied on the mechanism of action and structure-activity relationship. Eventually, we hope this project will discover a highly isoform-selective, potent and novel lead compound, which laids the foundation for the discovery of novel CARM1-targeted antitumor drugs.

蛋白精氨酸甲基转移酶CARM1在癌症发生发展中发挥着至关重要的角色，已成为新兴的癌症治疗靶点。开发亚型选择性的CARM1抑制剂对于癌症的靶向治疗具有重要意义。前期研究中，我们发现了一类具有一定亚型选择性且具有抗肿瘤作用的新型CARM1小分子抑制剂，结合于底物结合位点，尤其作用于已知的选择性口袋。进一步蛋白结构分析发现，底物结合位点还存在潜在的新选择性口袋。据此，本项目提出利用该新口袋，基于前期发现的小分子抑制剂进行合理药物设计，使其同时作用于新旧两个选择性口袋，以提高该类化合物的亚型选择性；对化合物进行体外体内生物活性评价、作用机制与构效关系研究，以期发现结构新颖且具有高亚型选择性、高活性的先导化合物，为新型CARM1靶向性抗肿瘤药物的发现奠定基础。

蛋白精氨酸甲基转移酶CARM1在癌症发生发展中发挥着至关重要的角色，已成为新兴的癌症治疗靶点,因此开发选择性的CARM1抑制剂对于癌症的靶向治疗具有重要意义。前期研究中，我们发现了一类具有一定CARM1选择性且具有抗肿瘤作用的新型CARM1小分子抑制剂。本项目主要采用基于结构的合理药物设计方法，针对底物结合位点的两个选择性口袋对先导化合物进行了结构优化，设计并合成了30个结构新颖的衍生物，发现了活性更高、选择性更好的化合物，并且阐明了这类抑制剂的构效关系，其中活性最好的化合物4-43的酶抑制IC50为57nM，抑制肿瘤细胞增殖的EC50达到670nM。此外，我们发现先导化合物本身具有良好的体内抗肿瘤疗效和较高的安全性，以此为分子探针进行抗肿瘤机制研究发现其可以通过特异性地抑制CARM1介导的雌激素诱导基因表达来抑制雌激素受体阳性乳腺癌的生长。以上研究结果表明本项目发现的新型CARM1抑制剂在开发新的乳腺癌靶向治疗方面具有良好的前景。