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

Neomorphic IDH2^R140Q 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^R140Q inhibitors. Among them, compound 36 was identified as the most promising inhibitor, with an IC₅₀ value 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/IDH2^R140Q cells. Furthermore, it showed reasonable pharmacokinetic properties with high bioavailability (F = 90.3%) and an appropriate half-life (T_1/2 = 6.4 h). In vivo, oral administration of compound 36 at a dose of 25 mg/kg effectively reduced D2HG levels in the tumor of TF-1/IDH2^R140Q xenograft mouse model. Besides, compound 36 displayed little effect on the hERG current. These results suggest that compound 36 has the potential to be an efficacious treatment for AML.