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 IDH1R132Hmutation 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.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baird
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bowen
authors.affiliation: Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Capka
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Gregg
authors.initials: G
authors.lastname: Chenail
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: YoungShin
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Dooley
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Farsidjani
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Fortin
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Darcy
authors.initials: D
authors.lastname: Kohls
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Raviraj
authors.initials: R
authors.lastname: Kulathila
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Fallon
authors.initials: F
authors.lastname: Lin
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: McKay
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Rodrigues
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sage
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: B Barry
authors.initials: BB
authors.lastname: Touré
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: van der Plas
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Wright
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Levell
authors.affiliation: Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: raymond.pagliarini@novartis.com.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Pagliarini
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D005977:Glutarates; D020033:Protein Isoforms; D054852:Small Molecule Libraries; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: 2-HG; 2-hydroxyglutarate; IDH1; IDH2; Isocitrate dehydrogenase; oncology; targeted therapy