7ONS

PARP1 catalytic domain in complex with isoquinolone-based inhibitor (compound 16)

7ONS の概要

• エントリーDOI: 10.2210/pdb7ons/pdb
• 関連するPDBエントリー: 7ONR 7ONT
• 分子名称: Poly [ADP-ribose] polymerase 1, 7-[[4-(1,5-dimethylimidazol-2-yl)piperazin-1-yl]methyl]-3-ethyl-1~{H}-quinolin-2-one, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: parp inhibitor, selectivity, structure-based drug design, synthetic lethal therapy, oncology, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79837.13

構造登録者

Schimpl, M.,Balazs, A.,Barratt, D.,Bista, M.,Chuba, M.,Degorce, S.L.,Di Fruscia, P.,Embrey, K.,Ghosh, A.,Gill, S.,Gunnarsson, A.,Hande, S.,Hemsley, P.,Heightman, T.D.,Illuzzi, G.,Lane, J.,Larner, C.,Leo, E.,Madin, A.,Martin, S.,McWilliams, L.,Orme, J.,Pachl, F.,Packer, M.,Pike, A.,Staniszewska, A.D.,Talbot, V.,Underwood, E.,Varnes, G.J.,Zhang, A.,Zheng, X.,Johannes, J.W. (登録日: 2021-05-25, 公開日: 2021-09-15, 最終更新日: 2024-05-01)

主引用文献

Johannes, J.W.,Balazs, A.,Barratt, D.,Bista, M.,Chuba, M.D.,Cosulich, S.,Critchlow, S.E.,Degorce, S.L.,Di Fruscia, P.,Edmondson, S.D.,Embrey, K.,Fawell, S.,Ghosh, A.,Gill, S.J.,Gunnarsson, A.,Hande, S.M.,Heightman, T.D.,Hemsley, P.,Illuzzi, G.,Lane, J.,Larner, C.,Leo, E.,Liu, L.,Madin, A.,Martin, S.,McWilliams, L.,O'Connor, M.J.,Orme, J.P.,Pachl, F.,Packer, M.J.,Pei, X.,Pike, A.,Schimpl, M.,She, H.,Staniszewska, A.D.,Talbot, V.,Underwood, E.,Varnes, J.G.,Xue, L.,Yao, T.,Zhang, K.,Zhang, A.X.,Zheng, X.
Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.
J.Med.Chem., 64:14498-14512, 2021

PubMed Abstract: Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

PubMed: 34570508
DOI: 10.1021/acs.jmedchem.1c01012

実験手法

X-RAY DIFFRACTION (1.97 Å)