6hmk
POLYADPRIBOSYL GLYCOHYDROLASE IN COMPLEX WITH PDD00016690
Structural highlights
FunctionPARG_HUMAN Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.[1] Publication Abstract from PubMedDNA damage repair enzymes are promising targets in the development of new therapeutic agents for a wide range of cancers and potentially other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG) plays a pivotal role in the regulation of DNA repair mechanisms; however, the lack of potent drug-like inhibitors for use in cellular and in vivo models has limited the investigation of its potential as a novel therapeutic target. Using the crystal structure of human PARG in complex with the weakly active and cytotoxic anthraquinone 8a, novel quinazolinedione sulfonamides PARG inhibitors have been identified by means of structure-based virtual screening and library design. 1-Oxetan-3-ylmethyl derivatives 33d and 35d were selected for preliminary investigations in vivo. X-ray crystal structures help rationalize the observed structure-activity relationships of these novel inhibitors. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides.,Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ J Med Chem. 2018 Dec 13;61(23):10767-10792. doi: 10.1021/acs.jmedchem.8b01407., Epub 2018 Nov 19. PMID:30403352[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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