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== Disease == | == Disease == | ||
[[http://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[http://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors. | [[http://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[http://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors. | ||
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== Publication Abstract from PubMed == | |||
High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model. | |||
Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.,Levell JR, Caferro T, Chenail G, Dix I, Dooley J, Firestone B, Fortin PD, Giraldes J, Gould T, Growney JD, Jones MD, Kulathila R, Lin F, Liu G, Mueller A, van der Plas S, Slocum K, Smith T, Terranova R, Toure BB, Tyagi V, Wagner T, Xie X, Xu M, Yang FS, Zhou LX, Pagliarini R, Cho YS ACS Med Chem Lett. 2016 Dec 16;8(2):151-156. doi: 10.1021/acsmedchemlett.6b00334., eCollection 2017 Feb 9. PMID:28197303<ref>PMID:28197303</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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<div class="pdbe-citations 5tqh" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 10:00, 9 March 2017
IDH1 R132H mutant in complex with IDH889IDH1 R132H mutant in complex with IDH889
Structural highlights
Disease[IDHC_HUMAN] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors. Publication Abstract from PubMedHigh throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model. Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.,Levell JR, Caferro T, Chenail G, Dix I, Dooley J, Firestone B, Fortin PD, Giraldes J, Gould T, Growney JD, Jones MD, Kulathila R, Lin F, Liu G, Mueller A, van der Plas S, Slocum K, Smith T, Terranova R, Toure BB, Tyagi V, Wagner T, Xie X, Xu M, Yang FS, Zhou LX, Pagliarini R, Cho YS ACS Med Chem Lett. 2016 Dec 16;8(2):151-156. doi: 10.1021/acsmedchemlett.6b00334., eCollection 2017 Feb 9. PMID:28197303[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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