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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.

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