Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2^R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia

Abstract

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 IC 50 value of 29 nM and more than 490-fold selectivity over wild-type IDH2. The compound significantly suppressed D2HG production (IC 50 = 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.

IDH2/R140Q mutation confers cytokine-independent proliferation of TF-1 cells by activating constitutive STAT3/5 phosphorylation

“…Targeting IDH2/R140Q is the main strategy for the treatment of mutated AML and works by restoring leukemia cell differentiation. Our previous studies identified several selective inhibitors of IDH2/R140Q that induce cellular differentiation in leukemia cells [ 6 , 7 ]. Although the approved IDH2/R140Q inhibitor enasidenib exhibits encouraging therapeutic effects in patients with IDH2/R140Q mutated AML [ 8 ], acquired resistance to enasidenib has been reported [ 9 ], and approximately 12% of enasidenib-treated patients developed IDH differentiation syndrome, a potentially lethal clinical entity [ 10 ].…”