新型IDH1突变体选择性抑制剂的发现及抗白血病活性和机制研究

"Personalized medicine" is a New Era of anti-cancer drugs development. One potential drug target is isocitrate dehydrogenase 1 (IDH1), a key metabolic enzyme of TCA cycle, which is mutated in multiple human cancers. Oncogenic properties of IDH1 mutation was presented through promoting leukemogenesis in vivo. But drug development targeted Mutant IDH1 is in the initial stage now. A key challenge is the development of drug strategies for selective and active inhibitor in terms of IDH1 mutant signatures. Preliminary work, based on IDH1/R132H which is the vast majority of IDH1 mutations in leukemia, we have established a high-throughput screening assay that utilized the ability of the IDH1/R132H mutant to produce R-2-hydroxyglutarate (2-HG). After random screening, five selective IDH1/R132H inhibitors identified through a high-throughput screen reduced 2-HG and promoted differentiation of leukemia cell. In this study, we will optimize the drug-like properties of known 5 inhibitors. Toward the aim of developing IDH1 mutant inhibitors, we will use approaches according to selectivity of IDH1 mutant, cellular metabolite, epigenetic effects, and the growth and differentiation of leukemia cells to identify the hit compounds quickly. And we hope these effects can not only provide new candidate for mutant IDH1-dependent cancer, but also benefit other researchers for further mutant IDH1 inhibitor development.

“个性化药物”是当前抗肿瘤药物研发新趋势。异柠檬酸脱氢酶1（IDH1）在多种肿瘤中突变率高，成为潜在的抗肿瘤个性化药物靶点，其中IDH1突变的致癌性在白血病上得到证实。目前国际相关药物开发工作刚刚开始，如何快速有效的发现高选择性、高活性的IDH1突变体抑制剂是药物研发的关键问题。前期我们建立在白血病中高突变率的IDH1/R132H突变体筛选模型，通过高通量筛选获得5个与阳性化合物抑制活性相当且结构新颖的化合物，初步细胞水平的功能与机制研究显示其能够降低细胞内IDH1突变导致的2-HG累积，并促进白血病细胞的分化。本项目拟在此基础上，进一步开展化合物结构改造，依据对IDH1突变酶的高选择性、突变引起的代谢产物和表观遗传的变化，结合白血病细胞增殖和分化功能指标的策略，发现IDH1突变体高选择性高活性的结构新颖的候选化合物，为针对IDH1/R132突变体的抗肿瘤药物研发提供新的思路和候选化合物。

“个性化药物”是当前抗肿瘤药物研发新趋势。异柠檬酸脱氢酶1（IDH1）在多种肿瘤中突变率高，成为潜在的抗肿瘤个性化药物靶点，其中IDH1突变的致癌性在白血病上得到证实。在过去几年，很多IDH1突变体抑制剂被报道，而AGI-120 (developed by Agios Pharmaceuticals, Cambridge, MA, USA)已于2018年7月FDA批准上市，而IDH305 (Novartis Pharmaceuticals, Basel, Switzerland)也进入临床研究。.本项目依据对IDH1突变酶的高选择性、突变引起的代谢产物和表观遗传的变化，结合白血病细胞增殖和分化功能指标的策略，发现IDH1突变体高选择性高活性的结构新颖的候选化合物。针对这个目标，我们发现了几个系列的结构母核，通过分子、细胞活性测试，发现能够抑制IDH1突变体，而不抑制其野生型酶，并且剂量依赖的抑制细胞内2-HG（突变体引起的代谢产物）的生成。进一步通过构效关系分析和分子模型模拟研究，证明其对IDH1突变体的靶向性。我们针对IDH1/R132突变体的抗肿瘤药物研发策略为研发该靶点化合物提供新的思路和候选化合物。