9SMO

Crystal Structure of human exonuclease 1 (Exo1) with DNA and compound ART5537

This is a non-PDB format compatible entry.

Summary for 9SMO

• Entry DOI: 10.2210/pdb9smo/pdb
• Related: 9SEB
• Descriptor: Exonuclease 1, DNA (5'-D(*CP*(GS)P*CP*TP*AP*GP*TP*CP*GP*TP*CP*AP*(TS))-3'), DNA (5'-D(P*AP*(SC)P*GP*AP*CP*TP*AP*GP*CP*(GS))-3'), ... (7 entities in total)
• Functional Keywords: exonuclease, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 47958.08

Authors

Toste Rego, A.,Pica, A.,Cornaciu, I.,Burgdorf, L.,Mann, S.E. (deposition date: 2025-09-08, release date: 2025-12-17, Last modification date: 2026-01-07)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.199 Å)