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

Abstract

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 “regulatory segment,” which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1404998
Resource Type:
Journal Article
Resource Relation:
Journal Name: Structure; Journal Volume: 25; Journal Issue: 3
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Xie, Xiaoling, Baird, Daniel, Bowen, Kimberly, Capka, Vladimir, Chen, Jinyun, Chenail, Gregg, Cho, YoungShin, Dooley, Julia, Farsidjani, Ali, Fortin, Pascal, Kohls, Darcy, Kulathila, Raviraj, Lin, Fallon, McKay, Daniel, Rodrigues, Lindsey, Sage, David, Touré, B. Barry, van der Plas, Simon, Wright, Kirk, Xu, Ming, Yin, Hong, Levell, Julian, and Pagliarini, Raymond A. Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity. United States: N. p., 2017. Web. doi:10.1016/j.str.2016.12.017.
Xie, Xiaoling, Baird, Daniel, Bowen, Kimberly, Capka, Vladimir, Chen, Jinyun, Chenail, Gregg, Cho, YoungShin, Dooley, Julia, Farsidjani, Ali, Fortin, Pascal, Kohls, Darcy, Kulathila, Raviraj, Lin, Fallon, McKay, Daniel, Rodrigues, Lindsey, Sage, David, Touré, B. Barry, van der Plas, Simon, Wright, Kirk, Xu, Ming, Yin, Hong, Levell, Julian, & Pagliarini, Raymond A. Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity. United States. doi:10.1016/j.str.2016.12.017.
Xie, Xiaoling, Baird, Daniel, Bowen, Kimberly, Capka, Vladimir, Chen, Jinyun, Chenail, Gregg, Cho, YoungShin, Dooley, Julia, Farsidjani, Ali, Fortin, Pascal, Kohls, Darcy, Kulathila, Raviraj, Lin, Fallon, McKay, Daniel, Rodrigues, Lindsey, Sage, David, Touré, B. Barry, van der Plas, Simon, Wright, Kirk, Xu, Ming, Yin, Hong, Levell, Julian, and Pagliarini, Raymond A. Wed . "Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity". United States. doi:10.1016/j.str.2016.12.017.
@article{osti_1404998,
title = {Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity},
author = {Xie, Xiaoling and Baird, Daniel and Bowen, Kimberly and Capka, Vladimir and Chen, Jinyun and Chenail, Gregg and Cho, YoungShin and Dooley, Julia and Farsidjani, Ali and Fortin, Pascal and Kohls, Darcy and Kulathila, Raviraj and Lin, Fallon and McKay, Daniel and Rodrigues, Lindsey and Sage, David and Touré, B. Barry and van der Plas, Simon and Wright, Kirk and Xu, Ming and Yin, Hong and Levell, Julian and Pagliarini, Raymond A.},
abstractNote = {Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 “regulatory segment,” which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.},
doi = {10.1016/j.str.2016.12.017},
journal = {Structure},
number = 3,
volume = 25,
place = {United States},
year = {Wed Mar 01 00:00:00 EST 2017},
month = {Wed Mar 01 00:00:00 EST 2017}
}