Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity

Xie, Xin; Baird, Daniel; Bowen, Kimberly Elizabeth; Čápka, Vladimı́r; Chen, Jinyun; Chenail, Gregg; Cho, YoungShin; Dooley, Julia; Farsidjani, Ali; Fortin, Pascal D.; Kohls, Darcy; Kulathila, Raviraj; Lin, Fallon; McKay, Daniel J.; Rodrigues, Lindsey Ulkus; Sage, David R.; Touré, B. Barry; Plas, Simon van der; Wright, Kirk; Xu, Ming; Yin, Hong; Levell, Julian; Pagliarini, Raymond

doi:10.1016/j.str.2016.12.017

Cited by 55 publications

(77 citation statements)

References 24 publications

(36 reference statements)

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“…The crystal structure of target protein, Isocitrate Dehydrogenases (IDH2), was recuperated from Protein Data Bank (PDB ID: 5SVN)and was fetched for further studies of docking process (Xie et al, 2017) (Figure 1). The 3D conformers of inhibitors having pubchem ID were saved in SDF format.…”

Section: Protein and Ligand Preparationmentioning

confidence: 99%

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

Sweta¹,

Khandelwal²,

Srinitha³

et al. 2019

Asian Pac J Cancer Prev

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According to the American Cancer Society (ACS), Acute Myeloid Leukemia (AML) is a group of hematological diseases, phenotypic and genetically heterogeneous, characterized by clonal expansion of myeloid with diminished capacity for differentiation. It is characterized by the fast growth of white blood cells, red blood cells, platelets, and it's a build-up in the bone marrow restricting the production of traditional blood cells. Once healthy bone marrow cells are replaced with the leukemic cells, it results in a decline in red blood cells, platelets, and healthy white blood cells. Mainly, symptoms that are seen in patients affected by AML are Weight loss, Fatigue, Fever, Night sweat, Loss of appetite, shortness of breath, natural bruising and bleeding, with lots of body

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Section: Protein and Ligand Preparationmentioning

confidence: 99%

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

Sweta¹,

Khandelwal²,

Srinitha³

et al. 2019

Asian Pac J Cancer Prev

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“…The α10 regulatory domain has been posited to be important for conferring selectivity for mutant IDH1 inhibitor binding (80). As D273 is located in this domain, we next asked if D273 mutants altered catalysis and inhibitor binding in the R132H IDH1 background.…”

Section: Resultsmentioning

confidence: 99%

“…The regulatory role of this domain likely differs when comparing WT and mutant IDH1, where in the latter form of the protein, unraveling of the 10 helix (80) and changes in water dynamics (82) have been posited to contribute to selectivity of inhibitor binding to mutant over WT IDH1. In contrast, in structures of mutant IDH2, this domain remains in the helical conformation in apo, holo, and inhibitor-bound forms (80,103). Interestingly, the D273 homolog in IDH2, D312, is located on the same side of the helix and only 5.3 Å from Q316 IDH2, a residue involved in acquired resistance to mutant IDH2 inhibitor binding.…”

Section: Discussionmentioning

confidence: 99%

An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity

Luna

Lesecq

White

et al. 2020

Preprint

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§This paper is dedicated to the memory of our dear colleague and friend, Michelle Evon Scott (1990Scott ( -2020. ABSTRACTIsocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP+-dependent conversion of isocitrate to α-ketoglutarate (α-KG) to provide critical cytosolic substrates and drive NADPH-dependent reactions like lipid biosynthesis and glutathione regeneration. In biochemical studies, the forward reaction is studied at neutral pH, while the reverse reaction is typically characterized in more acidic buffers. This led us to question whether IDH1 catalysis is pH-regulated, which would have functional implications under conditions that alter cellular pH, like apoptosis, hypoxia, cancer, and neurodegenerative diseases. Here, we show evidence of catalytic regulation of IDH1 by pH, identifying a trend of increasing kcat values for α-KG production upon increasing pH in the buffers we tested. To understand the molecular determinants of IDH1 pH sensitivity, we used the pHinder algorithm to identify buried ionizable residues predicted to have shifted pKa values. Such residues can serve as pH sensors, with changes in protonation states leading to conformational changes that regulate catalysis. We identified an acidic residue buried at the IDH1 dimer interface, D273, with a predicted pKa value upshifted into the physiological range. D273 point mutations had decreased catalytic efficiency and, importantly, loss of pH-regulated catalysis. Based on these findings, we conclude that IDH1 activity is regulated, at least in part, by pH. We show this regulation is mediated by at least one buried acidic residue ~12 Å from the IDH1 active site. By establishing mechanisms of regulation of this well-conserved enzyme, we highlight catalytic features that may be susceptible to pH changes caused by cell stress and disease.

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“…The structure of IDH2-R172K is very different to that of IDH2-R140Q. 30 All mIDH2 inhibitors have been designed to target IDH2-R140Q, and show very weak inhibitory effects on IDH2-R172K. 15,16 Unlike these inhibitors, TQ05310 very strongly inhibited IDH2-R172K, significantly inhibiting enzymatic activity and 2-HG production, and inducing differentiation in cells transfected with IDH2-R172K.…”

Section: Discussionmentioning

confidence: 99%

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

Gao

Zhu

et al. 2019

Cancer Science

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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.

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Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity

Cited by 55 publications

References 24 publications

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity

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

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