新型苯并咪唑类IDH2 R140Q选择性抑制剂的设计、合成及抗AML活性研究

Isocitrate dehydrogenase (IDH) is a metabolic enzyme that interconverts isocitrate and α-ketoglutarate, but cancer-associated point mutation in IDH2 R140Q confer a neomorphic activity that allows reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate, leading to acute myeloid leukemia (AML). AGI-6780 is a potent IDH2 R140Q inhibitor with poor selectivity. Based on the lead compound AGI-6780, this project is going to design and synthesize six new series of benzimidazoles IDH2 R140Q selective inhibitors with the computer-aided drug design tool and scafflod hopping strategy. The compounds will be screened by various bioassays, such in vitro anti-IDH2 R140Q activty, MTT method, and in vivo animals test, to obtain 1-2 potent inhibitors of IDH2 R140Q with high specificity, which will provide support for promoting the development of China’s targeted anti-AML drugs, and provide a scientific basis for individualized treatment of AML.

异柠檬酸脱氢酶的突变体IDH2 R140Q不但不能催化异柠檬酸的氧化脱羧生成α-酮戊二酸，反而将α-酮戊二酸还原为致癌代谢产物(R)--羟基戊二酸，导致急性髓细胞白血病（AML）的发生和恶化，是治疗AML药物的最新靶点。文献报道，AGI-6780对IDH2 R140Q有抑制作用，但同时抑制野生型IDH2，选择性并不理想。本项目以AGI-6780为先导，根据骨架跃迁的药物设计思路，借助计算机辅助药物设计的手段，拟设计合成6个系列新型苯并咪唑类IDH2 R140Q选择性抑制剂，结合细胞、分子和实验动物水平上的活性筛选，通过设计、合成和筛选循环的进化策略，以期发现 1-2 个活性强、选择性高的IDH2 R140Q抑制剂，为开启和推动我国抗AML的靶向药物研发提供支持，为AML的个体化治疗提供科学依据。

异柠檬酸脱氢酶的突变体IDH2 R140Q不但不能催化异柠檬酸的氧化脱羧生成α-酮戊二酸，反而将α-酮戊二酸还原为致癌代谢产物(R)-α-羟基戊二酸，导致急性髓细胞白血病（AML）的发生和恶化，是治疗AML药物的最新靶点。文献报道，AGI-6780对IDH2 R140Q有抑制作用，但同时抑制野生型IDH2，选择性并不理想。本项目以AGI-6780为先导，根据骨架跃迁的药物设计思路，借助计算机辅助药物设计的手段，设计合成一系列新型苯并咪唑类IDH2 R140Q选择性抑制剂，体外酶水平抑制活性结果表明，多个化合物达到纳摩尔级的抑制水平。其中，7o活性最好，IC50到达了0.2615±0.04803μM，相对于IDH2 WT选择性指数SI>382，为开启和推动我国抗AML的靶向药物研发提供支持，为AML的个体化治疗提供科学依据。