Pharmacological characterization of TQ 05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants

Isocitrate dehydrogenase 2 ( IDH 2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. AG ‐221, an inhibitor primarily targeting the IDH 2‐R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, AG ‐221 has weak inhibitory activity toward IDH 2‐R172K, a mutant form of IDH 2 with more severe clinical manifestations. Herein, we report TQ 05310 as the first mutant IDH 2 inhibitor that potently targets both IDH 2‐R140Q and IDH 2‐R172K mutants. TQ 05310 inhibited mutant IDH 2 enzymatic activity, suppressed (R)‐2‐hydroxyglutarate (2‐ HG ) production and induced differentiation in cells expressing IDH 2‐R140Q and IDH 2‐R172K, but not in cells expressing wild‐type IDH 1/2 or mutant IDH 1. TQ 05310 bound to both IDH 2‐R140Q and IDH 2‐R172K, with Q316 being the critical residue mediating the binding of TQ 05310 with IDH 2‐R140Q, but not with IDH 2‐R172K. TQ 05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2‐ HG production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of TQ 05310, and provide new insight into the development of novel mutant IDH 2 inhibitors.