9i58
Crystal structure of DNPH1 bound by compound 31.
Structural highlights
FunctionDNPH1_HUMAN Catalyzes the cleavage of the N-glycosidic bond of deoxyribonucleoside 5'-monophosphates to yield deoxyribose 5-phosphate and a purine or pyrimidine base. Deoxyribonucleoside 5'-monophosphates containing purine bases are preferred to those containing pyrimidine bases (By similarity).[HAMAP-Rule:MF_03036] Publication Abstract from PubMedDNPH1 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 pIC(50) 4.7), we identified compound 38 as a very potent inhibitor of DNPH1 (pIC(50) 9.3) using DNPH1 X-ray structure-guided drug design. Compound 38 demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC(50) 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line. Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2'-Deoxynucleoside 5'-Monophosphate Glycosidase (DNPH1).,Barlaam B, Alonso-Crisostomo L, Anderson NA, Argyrou A, Astles PC, Cadogan EB, Carlino L, Collie GW, Davies NL, Hall J, Kitching L, Li X, Michopoulos F, Milbradt AG, Nikkila J, Northall S, O'Connor MJ, Pei X, Shaw J, Slade D, Southgate H, Stead D, Stubbs CJ, Whitehurst BC, Xing B, Yuan Y, Zhou J J Med Chem. 2025 Nov 5. doi: 10.1021/acs.jmedchem.5c02356. PMID:41194588[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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