Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia
Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia
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DOI：
10.1021/acs.jmedchem.3c00835
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发表时间：
2023-09-14
影响因子：
7.3
通讯作者：
Cao，Peng
中科院分区：
文献类型：
--
作者：
Wei，Qingyun;Yao，Kun;Cao，Peng
新变体IDH 2 R140 Q突变常见于急性髓系白血病（AML），抑制其活性已被证实是治疗AML的有效方法。在此，我们报道了一系列高效和选择性IDH 2 R140 Q抑制剂。其中，化合物36被鉴定为最有希望的抑制剂，其IC 50值为29 nM，选择性超过野生型IDH 2的490倍。该化合物显著抑制TF-1/IDH 2 R140 Q细胞中D2 HG的产生（IC 50 = 10 nM）并诱导分化。体内研究表明，口服25 mg/kg的化合物36可有效降低TF-1/IDH 2 R140 Q移植瘤小鼠体内D2 HG的水平，生物利用度为90.3%，半衰期为6.4 h。此外，化合物36对hERG电流影响不大。这些结果表明化合物36具有成为AML的有效治疗的潜力。
Neomorphic IDH2R140Qmutation 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 IDH2R140Qinhibitors. Among them, compound36was identified as the most promising inhibitor, with an IC50value of 29 nM and more than 490-fold selectivity over wild-type IDH2. The compound significantly suppressed D2HG production (IC50= 10 nM) and induced differentiation in TF-1/IDH2R140Qcells. Furthermore, it showed reasonable pharmacokinetic properties with high bioavailability (F= 90.3%) and an appropriate half-life (T1/2= 6.4 h).In vivo, oral administration of compound36at a dose of 25 mg/kg effectively reduced D2HG levels in the tumor of TF-1/IDH2R140Qxenograft mouse model. Besides, compound36displayed little effect on the hERG current. These results suggest that compound36has the potential to be an efficacious treatment for AML.