Discovery of ART5537: A Potent and Selective Small-Molecule Probe for EXO1
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 <i>BRCA1</i>-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 <b>ART5537</b>, 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 <b>ART5537</b> is driven exclusively by EXO1. Furthermore, we show that <b>ART5537</b> sensitizes cancer cells to ionizing radiation (IR) and synergizes with PARP inhibitors (PARPi).
Authors
- Diego Grande (ORCID: https://orcid.org/0000-0001-6770-9274)
- Claire McWhirter (ORCID: https://orcid.org/0000-0003-3316-205X)
- Helen M.R. Robinson (ORCID: https://orcid.org/0000-0003-0414-0740)
- Frank T. Zenke (ORCID: https://orcid.org/0000-0002-2226-3755)
- Ulrich Pehl (ORCID: https://orcid.org/0000-0003-2559-723X)
- Christin Rakers (ORCID: https://orcid.org/0000-0002-5668-6844)
- F.J. Sorrell (ORCID: https://orcid.org/0000-0001-9211-5590)
- Sam E. Mann (ORCID: https://orcid.org/0009-0007-7333-6196)
- Julien Lefranc (ORCID: https://orcid.org/0000-0002-2116-9425)
- Maria Filipa Pinto (ORCID: https://orcid.org/0000-0002-6337-3459)
- Elias Elinati (ORCID: https://orcid.org/0000-0002-4364-9358)
- Lerin Geo (ORCID: https://orcid.org/0009-0004-3688-1820)
- Ana Toste Rêgo (ORCID: https://orcid.org/0000-0002-8584-3386)
- Lars T. Burgdorf
- Andrea Pica (ORCID: https://orcid.org/0000-0002-8736-8742)
- Irina Cornaciu (ORCID: https://orcid.org/0000-0001-6597-754X)
- Dániel Schwarz (ORCID: https://orcid.org/0000-0002-9017-8245)
- Bruce Follows
- Bethany Mason (ORCID: https://orcid.org/0000-0002-1157-0469)
- Eeson Rajendra (ORCID: https://orcid.org/0000-0002-5301-054X)
- Alessandro Galbiati (ORCID: https://orcid.org/0000-0002-8795-7934)
- Catherine Jorand‐Lebrun
- Robert A. Heald (ORCID: https://orcid.org/0000-0003-3425-7130)
- Jörg Bomke
- Owen A. Davis (ORCID: https://orcid.org/0000-0002-7053-7079)
- Birgitta Leuthner (ORCID: https://orcid.org/0009-0000-5476-7854)
- Graeme C.M. Smith (ORCID: https://orcid.org/0000-0001-8320-4057)
- Carl Petersson (ORCID: https://orcid.org/0000-0003-2560-9560)
- Djordje Müsil (ORCID: https://orcid.org/0000-0001-7889-2940)
- Claudio A. Lademann
Institutions
- Babraham Institute (GB)
- Merck KGaA, Darmstadt (Germany) (DE)
- CEA Grenoble (FR)
- Ono Pharmaceutical (United States) (US)
- Research & Development Institute (US)
- Merck Serono S.p.A. (Italy) (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-12-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02593
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00