Wu Fangrui, Cheng Gang, Yao Yuan, Kogiso Mari, Jiang Hong, Li Xiao-Nan, Song Yongcheng
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States.
Department of Pediatrics-oncology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States.
Med Chem. 2018;14(7):715-724. doi: 10.2174/1573406414666180524093659.
R132H mutation of isocitrate dehydrogenase 1 (IDH1) is found in ~75% of low-grade gliomas and secondary glioblastomas as well as in several other types of cancer. More chemotypes of inhibitors of IDH1(R132H) are therefore needed.
The study aimed to develop a new class of IDH1(R132H) inhibitors as potent antitumor agents.
A biochemical assay was developed to find inhibitors of IDH1(R132H) mutant enzyme. Chemical synthesis and structure-activity relationship studies were used to find compounds with improved potency. Antitumor activities of selected compounds were evaluated.
A series of aromatic sulfonamide compounds was found to be novel, potent inhibitors of IDH1(R132H) with Ki values as low as 0.6 µM. Structure-activity relationships of these compounds are discussed. Enzyme kinetics studies showed that one compound is a competitive inhibitor against the substrate α-KG and a non-competitive inhibitor against the cofactor NADPH. Several inhibitors were found to have no activity against wild-type IDH1, showing a high selectivity. Two potent inhibitors exhibited strong activity against proliferation of BT142 glioma cells with IDH1 R132H mutation, while these compounds did not significantly affect the growth of glioma cells without IDH1 mutation.
This novel series of IDH1(R132H) inhibitors have potential to be further developed for the treatment of glioma with IDH1 mutation.
异柠檬酸脱氢酶1（IDH1）的R132H突变存在于约75%的低级别胶质瘤和继发性胶质母细胞瘤以及其他几种类型的癌症中。因此，需要更多化学类型的IDH1（R132H）抑制剂。
本研究旨在开发一类新型的IDH1（R132H）抑制剂作为有效的抗肿瘤药物。
建立了一种生化检测方法来寻找IDH1（R132H）突变酶的抑制剂。通过化学合成和构效关系研究来寻找活性增强的化合物，并对所选化合物的抗肿瘤活性进行评估。
发现一系列芳香族磺酰胺化合物是新型、有效的IDH1（R132H）抑制剂，其抑制常数（Ki）值低至0.6 μM。讨论了这些化合物的构效关系。酶动力学研究表明，一种化合物是底物α-酮戊二酸（α-KG）的竞争性抑制剂和辅因子烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的非竞争性抑制剂。发现几种抑制剂对野生型IDH1无活性，显示出高选择性。两种强效抑制剂对携带IDH1 R132H突变的BT142胶质瘤细胞的增殖具有强烈抑制活性，而这些化合物对无IDH1突变的胶质瘤细胞生长没有显著影响。
这一系列新型IDH1（R132H）抑制剂有潜力进一步开发用于治疗IDH1突变的胶质瘤。
