Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants

Abstract

Isocitrate dehydrogenase 2 (IDH2), 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 IDH2‐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 IDH2‐R172K, a mutant form of IDH2 with more severe clinical manifestations. Herein, we report TQ05310 as the first mutant IDH2 inhibitor that potently targets both IDH2‐R140Q and IDH2‐R172K mutants. TQ05310 inhibited mutant IDH2 enzymatic activity, suppressed (R)‐2‐hydroxyglutarate (2‐HG) production and induced differentiation in cells expressing IDH2‐R140Q and IDH2‐R172K, but not in cells expressing wild‐type IDH1/2 or mutant IDH1. TQ05310 bound to both IDH2‐R140Q and IDH2‐R172K, with Q316 being the critical residue mediating the binding of TQ05310 with IDH2‐R140Q, but not with IDH2‐R172K. TQ05310 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 TQ05310, and provide new insight into the development of novel mutant IDH2 inhibitors.

Point Mutation Specific Antibodies in B-Cell and T-Cell Lymphomas and Leukemias: Targeting IDH2, KRAS, BRAF and Other Biomarkers RHOA, IRF8, MYD88, ID3, NRAS, SF3B1 and EZH2

“…Other enzymes that could be affected by overproduction of 2-HG include enzymes involved in histone methylation and DNA methylation. The effects of these mutations in the IDH2 gene are linked to leukemogenesis and potentially solid cancers [ 13 , 57 ].…”

“…However, enasidenib was designed for, and is most effective against, the IDH2 R140Q mutation. One inhibitory compound in development, labeled TQ05310, showed significant efficacy in inhibiting IDH2 R172K as well as IDH2 R140Q [ 57 ].…”

4’-O-Methylbroussochalcone B as a novel tubulin polymerization inhibitor suppressed the proliferation and migration of acute myeloid leukaemia cells

“…Improvements in supportive care have increased overall survival rates in younger patients (< 15 years of age) to more than 60%, however, 40% relapses requiring salvage therapy ultimately [ 18 ]. Extensive research have revealed that chemotherapy drugs might be an effective strategy to treat human AML [ 19 ]. Cullen corylifolium is a plant widely used in traditional Chinese medicine for its stomachic, anthelmintic, and diuretic properties [ 20 ].…”

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review)

“…IDH2-mutated cells have significantly increased sensitivity to IL-1β signaling, which may be a potential therapeutic target (32). Furthermore, there are drugs in various stages of clinical development for the treatment of AML with mutated IDH2 proteins, such as AG-221 (enasidenib) (33), AGI-6780 (34), CP-17 (34), TQ05310 (35) and AG-881 (36). AG-221 is an oral, valid, selective inhibitor of mutated IDH2 that has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory leukemia with IDH2 gene mutations.…”