全新结构的丙酮酸脱氢酶激酶抑制剂的发现及其抗肿瘤活性研究

丙酮酸脱氢酶激酶（pyruvate dehydrogenase kinases, PDKs）是肿瘤代谢的关键节点酶，作为抗肿瘤药物靶点极具潜质。然而以PDKs为靶点的临床在研分子极少，开发基于该靶点的抗肿瘤药物迫在眉睫。本项目根据抑制PDK1激酶活性的高通量筛选和多种生物活性数据，确定苯并噁嗪酮衍生物13为先导化合物，然后基于靶点晶体结构对该化合物进行合理的结构修饰与优化，提高其与靶点PDK1的亲和力和抑制肿瘤生长的活性，最后对最具潜力活性分子进行深入的体内外生物学机制研究。通过本项目的实施，有望开发出高活性、低毒性、结构全新的PDK1抑制剂，为开发该靶点的临床抗肿瘤药物奠定基础。

Pyruvate dehydrogenase kinases (PDKs) play a crucial role in cancer metabolism, which are potential anticancer drug targets. Currently, few PDK inhibitors are studied in clinical trials, thus there is an urgent need to develop PDK inhibitors as anticancer drugs. This project aims to develop novel PDK inhibitors as anticancer drugs, with benzoxazine ketone derivative 13 as a lead which was identified from PDK1 kinase inhibition based high throughput screening and multiple biological activity assays. We will modify and optimize 13 to improve its PDK1 binding affinity and anticancer activity based on its target crystal structure. At last, we will select the most potent compound to study its biological roles in vitro and in vivo. We expect to discover novel PDK1 inhibitors with high potency and low toxicity from this project as promising preclinical candidates for cancer treatment.