雄激素受体降解和雄激素合成酶抑制双重功能化合物的设计、合成及构效关系研究

雄激素及其受体信号通路过度活化是男性常见恶性肿瘤前列腺癌发生发展的根本原因。诱导目标靶标蛋白泛素降解是一种全新的药物研发策略，虽然还面临巨大挑战，但已受到学术界的空前重视。本课题拟在申请者现有工作的基础上，采用基于结构生物学知识的合理药物设计策略，并结合传统药物化学结构优化技术，针对性地解决阿比特龙缺乏雄激素受体降解活性、对CYP酶亚型选择性差、代谢性不理想的缺陷，设计合成四个系列共计约80个具有雄激素受体降解和雄激素合成酶抑制双重功能的新型甾体化合物，并深入研究其构效（受体降解活性、合成酶抑制活性、体内外抗前列腺癌增殖活性）、构代及构毒关系，重点探索甾体结构与雄激素受体降解活性之间的规律性，争取获得1-2个具有强大雄激素受体降解活性和强效雄激素合成酶抑制活性，CYP酶选择性好、代谢性质优良的候选化合物，为最终开发出新一代多功能雄激素受体降解剂用于治疗前列腺癌患者奠定坚实的知识基础。

Overactivation of androgen and its receptor signaling pathway is the root cause of prostate cancer in male malignant tumors. Inducing the ubiquitination degradation of target protein is a new strategy for drug development, although faced a great challenge, it has received unprecedented attention from the academic circles. Based on our previous researches, we will design and synthesis four series of about 80 novel steroid compounds with dual functions of androgen receptor degradation and androgen synthase inhibition through the rational drug design strategy based on structural biology knowledge and the traditional medicine chemical structure optimization technology, aimed at solving the defects of abiraterone, such as lack of androgen receptor degradation activity, poor selectivity to CYP subtype and poor metabolism. The structure-activity (receptor degradation activity, synthetase inhibitory activity, resistance to prostate cancer in vivo and in vitro proliferation activity)/metabolism/toxicity relationship of these compounds will be deeply researched, especially focused on the regularity between steroid structure and androgen receptor degradation activity, and we expect to obtain 1-2 potential candidate chemicals with strong androgen receptor degradation activity , potent androgen synthetase inhibitory activities, good CYP enzyme selectivity and excellent metabolic property . The results of this research will build up a solid knowledge for the discovery of a new generation of multi-function androgen receptor degraders for the treatment of prostate cancer patients .