6o2z: Difference between revisions
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==Crystal structure of IDH1 R132H mutant in complex with compound 32== | |||
<StructureSection load='6o2z' size='340' side='right'caption='[[6o2z]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6o2z]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O2Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O2Z FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LJV:6-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methylpyridine-3-carbonitrile'>LJV</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6o2z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o2z OCA], [http://pdbe.org/6o2z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o2z RCSB], [http://www.ebi.ac.uk/pdbsum/6o2z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o2z ProSAT]</span></td></tr> | |||
</table> | |||
== 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo ADME properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials. | |||
Discovery and Optimization of Quinolinone Derivatives as Potent, Selective and Orally Bioavailable mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.,Lin J, Lu W, Caravella JA, Campbell AM, Diebold RB, Ericsson A, Fritzen E, Gustafson GR, Lancia DR, Shelekhin T, Wang Z, Castro J, Clarke A, Gotur D, Josephine HR, Katz M, Diep H, Kershaw M, Yao L, Kauffman G, Hubbs SE, Luke GP, Toms AV, Wang L, Bair KW, Barr KJ, Dinsmore CJ, Walker D, Ashwell S J Med Chem. 2019 Jun 14. doi: 10.1021/acs.jmedchem.9b00362. PMID:31199148<ref>PMID:31199148</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6o2z" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Lin, J]] | [[Category: Lin, J]] | ||
[[Category: Toms, A | [[Category: Toms, A V]] | ||
[[Category: Allosteric inhibitor]] | |||
[[Category: Idh1]] | |||
[[Category: Inhibitor complex]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Oxidoreductase-inhibitor complex]] | |||