Highly recurrent somatic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 enzymes have been identified in a variety of tumor types including GBM and glioma subtypes, acute myelogenous leukemia, chondrosarcoma, and cholangiocarcinoma, among others. Mutant IDH proteins gain a novel function: the production of the “oncometabolite” 2-hydroxyglutarate (2-HG), which accumulates in the tumors of affected patients. The similarity of 2-HG to a-ketoglutarate, a cofactor required for the function of a large number of cellular enzymes, has led to the hypothesis that 2-HG may alter the function of one or more of these enzymes. Current literature has shown that 2-HG is able to inhibit a number of epigenetic factors (i.e. Jmj-domain histone demethylases, and the TET family of methylcytosine oxidases) though most of these studies have been carried out using over-expression systems that can potentially force non-relevant phenotypes. To this end, we explored histone methylation changes in a variety of cells that harbor endogenous heterozygous IDH1/2 mutations. Using an LC-MS based method to detect histone modifications, we profiled IDH MUT vs. WT cells to evaluate which global histone methylation changes correlated with mutant IDH status and whether these changes were widespread or discrete. This unbiased search highlighted IDH-dependent modifications of Histone 3 on Lysine 9 (H3K9) as the histone mark of highest interest for further study. We followed up by assessing the sufficiency and necessity of IDH mutation and 2-HG to alter H3K9 methylation using immunoblotting techniques. Our results suggest that H3K9 methylation is particularly sensitive to mutant IDH and 2-HG, which may give us further insight into the mechanism of how mutant IDH drives tumorgenicity. Citation Format: Fallon Lin, Veronica Saenz-Vash, Huili Zhai, Joy Fletcher, Mike Acker, David Jiang, John Gounarides, Julian Levell, Raymond Pagliarini. IDH mutations and 2-HG selectively affect histone methylation in the endogenous setting. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A20.
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator due to its role in the programmed cell death PD-L1/PD-1 pathway. Small molecule inhibition of SHP2 has been widely investigated including our previous reports describing SHP099, which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies led to the identification of multiple, potent inhibitor chemotypes, an additional and distinct allosteric binding site, and the identification of SHP394, an orally efficacious inhibitor of SHP2 with improved potency and enhanced pharmacokinetic properties. Overall, this work improves upon our previously described allosteric inhibitors, and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism. Citation Format: Matthew J. LaMarche, Jeff Bagdanoff, Mike Acker, Ying-Nan Chen, Homan Chan, Michael Dore, Brant Firestone, Michelle Fodor, Jorge Garcia-Fortanet, Murphy Hentemann, Mitsunori Kato, Robert Koenig, Laura La Bonte, Shumei Liu, Movarid Mohseni, Rukundo Ntaganda, Patrick Sarver, Troy Smith, Martin Sendzik, Travis Stams, Stan Spence, Chris Towler, Hongyun Wang, Ping Wang, Sarah Williams, Zhouliang Chen, Huaixiang Hao, Gang Liu, Chen Liu, Eric McNeill, Bing Yu. Allosteric SHP2 phosphatase inhibition: Multiple mechanisms and chemotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-005.
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