6HML

POLYADPRIBOSYL GLYCOSIDASE IN COMPLEX WITH PDD00017299

6HML の概要

• エントリーDOI: 10.2210/pdb6hml/pdb
• 分子名称: Poly(ADP-ribose) glycohydrolase, 1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-[[(1-methylcyclopropyl)amino]-bis(oxidanyl)-$l^{4}-sulfanyl]-3-[(1-methylpyrazol-4-yl)methyl]quinazoline-2,4-dione, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 62315.93

構造登録者

Tucker, J.A.,Barkauskaite, E. (登録日: 2018-09-12, 公開日: 2018-11-14, 最終更新日: 2024-01-24)

主引用文献

Waszkowycz, B.,Smith, K.M.,McGonagle, A.E.,Jordan, A.M.,Acton, B.,Fairweather, E.E.,Griffiths, L.A.,Hamilton, N.M.,Hamilton, N.S.,Hitchin, J.R.,Hutton, C.P.,James, D.I.,Jones, C.D.,Jones, S.,Mould, D.P.,Small, H.F.,Stowell, A.I.J.,Tucker, J.A.,Waddell, I.D.,Ogilvie, D.J.
Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides.
J.Med.Chem., 61:10767-10792, 2018

PubMed Abstract: DNA 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.

PubMed: 30403352
DOI: 10.1021/acs.jmedchem.8b01407

実験手法

X-RAY DIFFRACTION (2.25 Å)