Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2′-Deoxynucleoside 5′-Monophosphate Glycosidase (DNPH1)
DNPH1 is a nucleotide pool sanitizer that cleaves 5-hydroxymethyl-2-deoxyuridine-5-monophosphate (hmdUMP), preventing incorporation of the correspondent non-natural nucleotide into DNA. Recent findings have demonstrated that loss of DNPH1 could potentiate the sensitivity of PARP inhibitors in homologous recombination repair (HRR)-deficient cancers. We report the optimization of a non-nucleoside-based series of DNPH1 inhibitors. Starting from a weak compound <b>1</b> (binding affinity pIC<sub>50</sub> 4.7), we identified compound <b>38</b> as a very potent inhibitor of DNPH1 (pIC<sub>50</sub> 9.3) using DNPH1 X-ray structure-guided drug design. Compound <b>38</b> demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC<sub>50</sub> 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line.
Authors
- Filippos Michopoulos (ORCID: https://orcid.org/0000-0002-3667-6147)
- Benjamin C. Whitehurst (ORCID: https://orcid.org/0000-0002-5485-1762)
- Nichola L. Davies (ORCID: https://orcid.org/0000-0003-4591-8264)
- Sarah Northall
- Alexander G. Milbradt
- Baoshan Xing (ORCID: https://orcid.org/0000-0003-2028-1295)
- Elaine B. Cadogan (ORCID: https://orcid.org/0000-0002-9757-8305)
- Mark J. O’Connor (ORCID: https://orcid.org/0000-0003-1823-625X)
- Gavin W. Collie (ORCID: https://orcid.org/0000-0002-0406-922X)
- Bernard C. Barlaam (ORCID: https://orcid.org/0000-0002-0904-7556)
- Darren Stead
- Luca Carlino (ORCID: https://orcid.org/0000-0003-3838-2051)
- Christopher J. Stubbs (ORCID: https://orcid.org/0000-0002-2373-5478)
- Niall A. Anderson (ORCID: https://orcid.org/0000-0001-8403-9698)
- Luz Alonso‐Crisostomo
- Desmond Slade (ORCID: https://orcid.org/0000-0001-5534-6664)
- Argyrides Argyrou (ORCID: https://orcid.org/0000-0003-3141-9122)
- Harriet Southgate (ORCID: https://orcid.org/0000-0002-6898-2819)
- Linda Kitching
- Jie Zhou (ORCID: https://orcid.org/0000-0002-8797-7214)
- Y. Z. Yuan (ORCID: https://orcid.org/0009-0005-9713-0868)
- X. Li
- Jenni Nikkilä (ORCID: https://orcid.org/0000-0003-1380-8781)
- James Hall (ORCID: https://orcid.org/0000-0002-8124-5434)
- Joseph Shaw (ORCID: https://orcid.org/0009-0002-4828-5693)
- Xue-Yuan Pei (ORCID: https://orcid.org/0000-0001-7083-9651)
- Peter C. Astles
Institutions
- AstraZeneca (United Kingdom) (GB)
- AstraZeneca (Brazil) (BR)
- AstraZeneca (Poland) (PL)
- Molecular Oncology (United States) (US)
- AstraZeneca (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02356
- Citations
- 1
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.05