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
  • 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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