Wei Qingyun, Yao Kun, Yang Jie, Zhou Qian, Liu Pengyu, Chen Jiao, Liu Haipeng, Lai Yisheng, Cao Peng
Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
J Med Chem. 2023 Sep 28;66(18):12894-12910. doi: 10.1021/acs.jmedchem.3c00835. Epub 2023 Sep 14.
Neomorphic IDH2 mutation is commonly found in acute myeloid leukemia (AML), and inhibiting its activity has been validated as an effective treatment for AML. Herein, we report a series of highly potent and selective IDH2 inhibitors. Among them, compound was identified as the most promising inhibitor, with an IC value of 29 nM and more than 490-fold selectivity over wild-type IDH2. The compound significantly suppressed D2HG production (IC = 10 nM) and induced differentiation in TF-1/IDH2 cells. Furthermore, it showed reasonable pharmacokinetic properties with high bioavailability ( = 90.3%) and an appropriate half-life ( = 6.4 h). , oral administration of compound at a dose of 25 mg/kg effectively reduced D2HG levels in the tumor of TF-1/IDH2 xenograft mouse model. Besides, compound displayed little effect on the hERG current. These results suggest that compound has the potential to be an efficacious treatment for AML.
新形态异柠檬酸脱氢酶2（IDH2）突变在急性髓系白血病（AML）中普遍存在，抑制其活性已被证实是治疗AML的有效方法。在此，我们报告了一系列高效且选择性的IDH2抑制剂。其中，化合物被确定为最有前景的抑制剂，其IC值为29 nM，对野生型IDH2的选择性超过490倍。该化合物显著抑制D2HG的产生（IC = 10 nM），并诱导TF-1/IDH2细胞分化。此外，它显示出合理的药代动力学性质，具有高生物利用度（= 90.3%）和适当的半衰期（= 6.4小时）。口服给予25 mg/kg剂量的化合物可有效降低TF-1/IDH2异种移植小鼠模型肿瘤中的D2HG水平。此外，化合物对hERG电流几乎没有影响。这些结果表明化合物有潜力成为治疗AML的有效药物。
