特异性BET溴结构域抑制剂的设计、合成及抗肿瘤活性研究

开发表观遗传调控的小分子药物是当今药物研究热点。作为表观遗传阅读器的溴结构域（BRD）可特异地识别乙酰化赖氨酸，从而调控基因转录。BRD蛋白与肿瘤和炎症等疾病的发生发展密切相关。近年来，许多大型国际制药公司和科研院所投入了大量精力开发针对家族中的BET溴结构域小分子抑制剂。虽有8小分子进入临床研究，但结构类型较为单一。因此，结构新颖、成药性好的BET抑制剂的发现仍尤为迫切。本研究以前期发现的活性较好的苯并吲哚-2-酮骨架为基础，采用基于结构的药物设计和骨架跃迁等方法，获得了两类骨架结构新颖的目标小分子。这两类小分子在保持高活性的同时，改进了前期先导化合物水溶性。我们将开展深入的构效关系研究，评价小分子的选择性、药效性和初步成药性。本课题的成功开展将为研究BET蛋白在癌症和炎症疾病等的治疗作用提供具有自主知识产权的、结构新颖、成药性好的先导化合物。

Epigenetic drug discovery is a field with enormous promise. Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-acetylated lysine residues. BRDs function as “reader” of acetyl-lysine marks and regulate gene transcription and chromatin organization. Dysfunction of BRD-containing proteins has been linked to the development of diverse diseases in particular to cancer and inflammation. Recently, some pharmaceutical and academic organizations put great effort in developing potent and highly specific inhibitors for BET family of BRDs, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. However, chemotypes of inhibitors are very limited, therefore, there is still urgent need for discovery of diverse chemotypes for BET family to produce safe and effective novel drugs. Hereby, we do our efforts to optimize the benzo[cd]indol-2(1H)-one scaffold from our previous study. For this purpose, we used structure-based drug design and scaffold hopping approaches to design new BET inhibitors with improved water solubility. We will investigate the structure-activity relationships and preliminary assess the selectivity, efficacy and drugability of small molecules. This study will provide attractive candidates with new scaffolds for the treatment of cancer and inflammation.