新型ERR-alpha小分子反向激动剂的设计、合成及抗乳腺癌活性研究

Estrogen receptor related receptor alpha (ERR alpha) is a dual effect tumor biomarker which can promote the growth of breast cancer and the new angiogenesis. Reverse agonist targeting ERRα will inhibit the growth of breast cancer and tumor angiogenesis. ERRα reverse agonists will provide a new strategy for molecular targeted therapy of breast cancer. Based on the SAR of 18 series and the reported ERRα reverse agonists, this project will put forward novel interacting characteristics between reverse agonists and ERRα. This project will also design series of novel small molecule inverse agonists using computer aided drug design strategy. Then the compounds will be synthesized and test the synthetic compounds. Inverse agonist activity evaluation against ERRα, the growth inhibition of breast cancer, the inhibition of the endothelial cell angiogenesis and pharmacokinetic evaluation in vitro and in vivo will all be assayed. This project is aimed to find 1-2 druggable and high potent small molecule inverse agonists of ERR alpha with better physical and chemical properties as anti-breast-cancer drug candidates distinguished by new mechanism. This study will lay the foundation for the discovery of novel anti- breast cancer drugs with the characteristics of broad-spectrum, anti-resistance, and inhibition of migration.

雌激素受体相关受体alpha（ERRα）是乳腺癌及新生血管生成的双重效应肿瘤生物标志物，靶向ERRα的反向激动剂兼具抗乳腺癌及抑制肿瘤血管新生的双重效应，将为乳腺癌分子靶向治疗提供新策略。本项目拟在发现的先导化合物18及文献报道的ERRα小分子反向激动剂与ERRα作用方式分析基础上，提出ERRα小分子反向激动剂与ERRα结合口袋全新的结合特点，运用计算机辅助药物设计与理性设计结合设计出全新反向激动剂对18进行进一步结构优化，对合成的化合物进行ERRα反向激动活性评价、抗乳腺癌体外体内药理学评价、ERRα反向激动剂抑制内皮细胞血管新生的效应评价，体外体内药代动力学评价。希望找到理化性质好、活性高、良好类药性的新型高效特异性ERRα反向激动剂1-2个作为新作用机制的抗乳腺癌候选药物。本项目将为具有广谱有效、抗耐药、抑制迁移等特点的抗乳腺癌药物的发现奠定基础。