ERRα反向激动剂的优化设计及抗肿瘤活性和机制研究

Estrogen-related receptors (ERRs) are orphan receptors that have no known endogenous ligands. Preliminary studies show that ERRs are closely related to glycolipid metabolism, osteoporosis, the development and migration of various tumors such as breast cancer and prostate cancer. Among of them ERRα is a new potential target for anticancer drugs. However, most of the ERR ligands, including the ERRα-type inverse agonists, have very limited scaffolds and no clear structure-activity relationship studies, and most of them are non-drug-like compounds with poor physic-chemical property and have no in vivo activity. Most importantly, There is no ERRs ligand in clinical trial at present. Based on our previous work, this project will take full advantage of the pre-established heterocyclic methodologies to explore and research the comprehensive structure-activity relationship, and finally get lead compounds or drug candidates with independent intellectual property rights, good physical and chemical properties and metabolic properties. Structure-activity relationship of ERRs ligand will be clarified. The lead compounds or drug candidates will be evaluated for the possibility of being drugs and be used as probes to further study the mechanism of drug action and ERRα biological function, to culture and determine ERR-ligand complex crystal structure. All these works will lay a solid foudation for development of drugs for those tumors lacking treatments such as triple negative breast cancer.

ERRs（雌激素相关受体）是内源性配体未知的孤儿核受体，初步研究表明ERRs与糖脂代谢、骨质疏松、多种肿瘤如乳腺癌、前列腺癌等的发生发展密切相关，其中ERRα是极具潜力的抗肿瘤药物新靶标。然而目前ERRs配体包括ERRα反相激动剂种类极其有限，也无明确的构效关系研究，且绝大多数配体无体内活性，或成药性质差，目前尚无ERRs激动剂或反相激动剂进入临床研究。本项目拟在前期工作基础上，以自己发现的苗头化合物为先导，充分利用前期建立的杂环方法学，基于ERRα复合物晶体结构，进行全面的构效关系研究，最终得到具有自主知识产权、理化和代谢性质优良、构效关系基本明确的药物先导物或候选药物，初步评价其成药性，并以其为探针进一步研究药物的作用机制和ERRα的生物学功能，为研发临床急需如三阴性乳腺癌的抗肿瘤药物奠定基础。

ERRs（雌激素相关受体）是内源性配体未知的孤儿核受体，初步研究表明ERRs与糖脂代谢.、骨质疏松、肿瘤如乳腺癌、前列腺癌等的发生发展密切相关。目前ERRs配体包括ERRα反向激动剂种类极其有限，也无明确的构效关系研究，且绝大多数配体无体内活性，或成药性质差，目前尚无ERRs激动剂或反向激动剂进入临床研究。本项目在前期工作基础上，设计合成了噻吩/噻唑类（约150个）、吲哚类（48个）、橙酮类（23个）三大类ERRα反向激动剂，并进行了5个新型杂环化合物库的构建，并进行了体外酶水平测试和肿瘤细胞增殖抑制实验。其中噻吩、吲哚类分子水平和细胞水平活性偏弱或代谢较差，未能进行深入研究。具有橙酮骨架的化合物活性最好，且具有优良的理化性质，分子水平活性达到纳摩尔的化合物就有近10个，但依然表现出微弱的抗肿瘤细胞增殖抑制活性。从本项目的研究结果来看，已报道的ERRα反向激动剂所呈现的抗肿瘤活性可能只是其off-target的作用，ERRα作为抗肿瘤药物靶标还需要更多的研究证据来支持。本项目得到的高活性配体显示了抗骨关节炎的潜力，其分子机制有待深入。值得注意的是抗骨关节炎药物是未被满足的临床需求，因此对已获得的高活性ERRα配体进行研究具有重要意义。本项目为进一步研究ERRα的生物学功能提供了高活性的分子探针，也为ERRα相关疾病的研究奠定了重要基础。本项目申请了专利2篇，发表了SCI论文5篇，完成了预定的任务。