9SEB

Crystal Structure of human exonuclease 1 (Exo1) with DNA and compound 20

これはPDB形式変換不可エントリーです。

9SEB の概要

• エントリーDOI: 10.2210/pdb9seb/pdb
• 関連するPDBエントリー: 9SMO
• 分子名称: DNA (5'-D(*CP*(GS)P*CP*TP*AP*GP*TP*CP*GP*TP*CP*AP*(PST))-3'), DNA (5'-D(P*AP*(SC)P*GP*AP*CP*TP*AP*GP*CP*(GS))-3'), Exonuclease 1, ... (8 entities in total)
• 機能のキーワード: exonuclease, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 47990.12

構造登録者

Toste Rego, A.,Pica, A.,Cornaciu, I.,Burgdorf, L.,Mann, S.E. (登録日: 2025-08-15, 公開日: 2025-12-17, 最終更新日: 2026-01-07)

主引用文献

Mann, S.E.,Davis, O.A.,Bomke, J.,Cornaciu, I.,Elinati, E.,Follows, B.,Galbiati, A.,Geo, L.,Grande, D.,Jorand-Lebrun, C.,Lademann, C.A.,Lefranc, J.,Leuthner, B.,Mason, B.,McWhirter, C.L.,Musil, D.,Pehl, U.,Petersson, C.,Pica, A.,Pinto, M.F.,Rajendra, E.,Rakers, C.,Rego, A.T.,Robinson, H.M.R.,Schwarz, D.,Smith, G.C.M.,Sorrell, F.J.,Zenke, F.T.,Heald, R.A.,Burgdorf, L.T.
Discovery of ART5537: A Potent and Selective Small-Molecule Probe for EXO1.
J.Med.Chem., 68:26432-26447, 2025

PubMed Abstract: Exonuclease 1 (EXO1) is emerging as a target of interest in oncology due to its involvement in multifaceted DNA metabolic processes, particularly in homologous recombination (HR). Evidence is building that -deficient cancers are sensitive to loss of EXO1, suggesting therapeutic potential for treating certain subsets of patients. However, EXO1 remains under-explored, with very few reported inhibitors, and there is a paucity of good quality, potent, and selective pharmacological tools to explore its biology. Here, we describe a metal-chelating fragment screen, which resulted in highly selective, submicromolar EXO1 hits. Our subsequent structure-based design and optimization led to the discovery of , the first highly potent and selective EXO1 inhibitor. We demonstrate that inhibition of EXO1 leads to potent suppression of HR in cells and that the HR inhibition of is driven exclusively by EXO1. Furthermore, we show that sensitizes cancer cells to ionizing radiation (IR) and synergizes with PARP inhibitors (PARPi).

PubMed: 41359073
DOI: 10.1021/acs.jmedchem.5c02593

実験手法

X-RAY DIFFRACTION (1.9 Å)