新型选择性ERRα小分子反向激动剂的设计、合成及其在乳腺癌治疗中的研究

Breast cancer is the most common malignancy diagnosed in female. The inevitably development of lapatinib-resistant HER2-amplified breast cancer and the lack of recognized molecular targets for TNBC have fostered a major effort to discover actionable clinical therapy to treat patients with these tumors. Study reveals that estrogen-related receptor α (ERRα) is closely associated with tumor development and progression, aggressiveness, drug resistance and unfavorable outcomes in breast cancer as a critical regulator for cellular energy metabolism, which implying that ERRα might be a valid candidate target for therapeutic treatment of breast cancer, especially TNBC and lapatinib-resistant breast cancer. However, few ERRα inverse agonists have been reported and no ERRα modulators have demonstrated efficacy in clinical trials. In our previous work, using selective ERRα inverse agonist C29 as lead compound, we have discovered a novel potent indolin-2-one derivative LS1-86 with IC50 value 5 nM, better than the positive control C29 (IC50 value 40 nM). As continuing research, this project intents to explore more potent ERRα inverse agonist, which may provide small molecule probes for further development of novel anti-breast cancer drugs targeting ERRα. At the same time, the mechanism of action of the novel active compounds on breast cancer cells will be explored, which may illuminate the biological function of ERRα reverse agonist in breast cancer. The project is hopefully to establish a new clinical treatment option for TNBC.

乳腺癌居女性恶性肿瘤发病率首位，临床上针对HER2高表达的Lapatinib耐药以及三阴乳腺癌(TNBC)尚缺乏有效治疗方案。研究发现，雌激素相关受体α(ERRα)是细胞能量代谢的关键性调节因子，与乳腺癌的发生发展、侵袭转移、耐药以及不良预后密切相关，是乳腺癌(尤其是Lapatinib耐药型乳腺癌和TNBC)治疗的潜在靶标，但目前尚无ERRα反向激动剂候选分子进入临床试验。项目前期以ERRα反向激动剂C29(TR-FRET IC50=40 nM)作为先导，已设计合成高活性苗头分子LS1-86 (IC50=5 nM)。在此基础上，本项目拟进一步开展LS1-86系列的构效关系研究，以探索和发现新型选择性ERRα反向激动剂，为靶向ERRα的抗肿瘤研究提供重要的小分子工具；其次，考察活性分子在乳腺癌治疗中的作用机制，促进ERRα反向激动剂在乳腺癌领域的机制研究，有望为乳腺癌的临床治疗提供全新方案。

乳腺癌居女性恶性肿瘤发病率首位，临床上针对HER2高表达的Lapatinib耐药以及三阴乳腺癌(TNBC)尚缺乏有效治疗方案。研究发现，雌激素相关受体α(ERRα)是细胞能量代谢的关键性调节因子，与乳腺癌的发生发展、侵袭转移、耐药以及不良预后密切相关，是乳腺癌(尤其是Lapatinib耐药型乳腺癌和TNBC)治疗的潜在靶标，但目前尚无ERRα反向激动剂候选分子进入临床试验。项目前期以ERRα反向激动剂C29(TR-FRET IC50=40 nM)作为先导，已设计合成高活性苗头分子LS1-86 (IC50=5 nM)。在此基础上，本项目进一步开展了LS1-86系列的构效关系研究，以探索和发现新型选择性ERRα反向激动剂，为靶向ERRα的抗肿瘤研究提供重要的小分子工具；其次，考察了活性分子在乳腺癌治疗中的作用机制，促进ERRα反向激动剂在乳腺癌领域的机制研究，有望为乳腺癌的临床治疗提供全新方案。.首先，我们采用骨架跃迁、生物电子等排等经典药物设计策略对苗头分子进行基于结构的药物设计，合成50余个结构新颖的吲哚环外烯酮类ERRα反向激动剂。大部分化合物在TR-FRET实验中均展现出纳摩尔级别的ERRα反向激动活性，其中IC50值低于10 nM的化合物共19个，显著优于阳性对照C29。但该类分子PK性质仍有待提高。其中，代表性分子1-7p和1-7n在db/db糖尿病小鼠模型中表现出较好的体内降糖活性和糖耐受能力；同时，相比于阳性分子罗格列酮，代表性分子1-7p和1-7n显著降低了对机体的肝脏损伤和心肌损伤。总之，该研究发现了一类骨架新颖的ERRα小分子反向激动剂，为阐明ERRα蛋白与其降糖功能提供了重要的实验依据，同时为靶向ERRα的抗代谢性疾病研究提供了重要的小分子工具。