2. Academic Validation
  3. Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2'-Deoxynucleoside 5'-Monophosphate Glycosidase (DNPH1)

Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2'-Deoxynucleoside 5'-Monophosphate Glycosidase (DNPH1)

  • J Med Chem. 2025 Nov 27;68(22):24381-24403. doi: 10.1021/acs.jmedchem.5c02356.
Bernard Barlaam 1,  Luz Alonso-Crisostomo 2,  Niall A Anderson 1,  Argyrides Argyrou 2,  Peter C Astles 1,  Elaine B Cadogan 1,  Luca Carlino 1,  Gavin W Collie 2,  Nichola L Davies 1,  James Hall 1,  Linda Kitching 2,  Xianxi Li 3,  Filippos Michopoulos 1,  Alexander G Milbradt 2,  Jenni Nikkilä 1,  Sarah Northall 2,  Mark J O'Connor 1,  Xiaohiu Pei 3,  Joseph Shaw 2,  Danial Slade 2,  Harriet Southgate 1,  Darren Stead 1,  Christopher J Stubbs 2,  Benjamin C Whitehurst 4,  Bin Xing 3,  Yihao Yuan 3,  Jie Zhou 3
Affiliations

Affiliations

  • 1 Oncology, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2 Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 3 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China.
  • 4 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
PMID: 41194588 DOI: 10.1021/acs.jmedchem.5c02356
Abstract

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 1 (binding affinity pIC50 4.7), we identified compound 38 as a very potent inhibitor of DNPH1 (pIC50 9.3) using DNPH1 X-ray structure-guided drug design. Compound 38 demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC50 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line.

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