Abstract
Neomorphic mutation R140Q in the metabolic enzyme isocitrate dehydrogenase 2 (IDH2) is found to be a driver mutation in cancers. Recent studies revealed that allosteric inhibitors could selectively inhibit IDH2/R140Q and induce differentiation of TF-1 erythroleukemia and primary human AML cells. However, the allosteric inhibition mechanism is not very clear. Here, we report the results from computational studies that AGI-6780 binds tightly with the divalent cation binding helices at the homodimer interface and prevents the transition of IDH2/R140Q homodimer to a closed conformation that is required for catalysis, resulting in the decrease of the binding free energy of NADPHs. If the allosteric inhibitor is removed, the original open catalytic center of IDH2/R140Q will gradually reorganize to a quasi-closed conformation and the enzymatic activity might recover. Unlike IDH2/R140Q, AGI-6780 locks one monomer of the wild-type IDH2 in an inactive open conformation and the other in a half-closed conformation, which can be used to explain the selectivity of AGI-6780. Our results suggest that conformational changes are the primary contributors to the inhibitory potency of the allosteric inhibitor. Our study will also facilitate the understanding of the inhibitory and selective mechanisms of AG-221 (a promising allosteric inhibitor that has been approved by FDA) for mutant IDH2.
Highlights
Oncogenic mutations contributing to the metabolic reprogramming are emerging hallmarks of various cancers[1]
As the enzymatic activity requires a conformational transition from an open to a closed conformation upon αKG binding[39], AGI-6780 locks the isocitrate dehydrogenase 2 (IDH2)/R140Q dimer in an open conformation incompatible with catalysis and inhibits the transformation of αKG to 2-HG
From the results we can see that the binding free energy of AGI-6780 with IDH2/R140QQ316A decreases to −47.08 kcal/mol, much lower than that with IDH2/R140Q (−62.37 kcal/mol, Table 3). This indicates that Q316 is crucial in the binding of AGI-6780 with IDH2/R140Q
Summary
Oncogenic mutations contributing to the metabolic reprogramming are emerging hallmarks of various cancers[1]. A series of inhibitors was reported to have promising preclinical efficacy and early-phase clinical activity in IDH1/2 mutant glioma and AML cells[18,19,20,21,22,23,24,25,26]. With IC50 of 23 nM for the homodimeric enzyme while 190 nM for the wild-type IDH2 (defined as IDH2/WT) It reduces intracellular 2-HG level and induces differentiation of TF-1 erythroleukemia and primary human AML cells carrying IDH2/R140Q mutation in vitro, providing evidence that inhibition of the mutant IDH2 enzyme can reverse some of the epigenetic changes it induces. Crystal structure reveals that AGI-6780 binds in an allosteric manner at the dimer interface of IDH2/R140Q, which is far from the mutated residue Q140 (Fig. 1), suggesting that the inhibition effect caused by AGI-6780 is rarely dependent on the contact with Q14019. To understand the selectivity of AGI-6780 for IDH2/R140Q over IDH2/WT, the dynamics of IDH2/WT in complex with AGI-6780 was characterized and compared with the system of IDH2/R140Q_AGI-6780
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