4OQA

Structure of Human PARP-1 bound to a DNA double strand break in complex with (2Z)-2-(2,4-dihydroxybenzylidene)-3-oxo-2,3-dihydro-1-benzofuran-7-carboxamide

4OQA の概要

• エントリーDOI: 10.2210/pdb4oqa/pdb
• 関連するPDBエントリー: 4DQY 4OPX 4OQB
• 分子名称: Poly [ADP-ribose] polymerase 1, DNA (26-MER), ZINC ION, ... (5 entities in total)
• 機能のキーワード: zinc finger, dna binding, parp, polymerase, dna repair, poly(adp-ribosyl)ation, transferase-dna-transferase inhibitor complex, transferase/dna/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus : P09874 P09874
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 191649.30

構造登録者

Pascal, J.M.,Steffen, J.D. (登録日: 2014-02-07, 公開日: 2014-07-02, 最終更新日: 2023-09-20)

主引用文献

Patel, M.R.,Bhatt, A.,Steffen, J.D.,Chergui, A.,Murai, J.,Pommier, Y.,Pascal, J.M.,Trombetta, L.D.,Fronczek, F.R.,Talele, T.T.
Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors.
J.Med.Chem., 57:5579-5601, 2014

PubMed Abstract: Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3',4'-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4'-hydroxyl/4'-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.

PubMed: 24922587
DOI: 10.1021/jm5002502

実験手法

X-RAY DIFFRACTION (3.65 Å)