Summary for 9I6E
| Entry DOI | 10.2210/pdb9i6e/pdb |
| Descriptor | 5-hydroxymethyl-dUMP N-hydrolase, 4-[[1,1-bis(oxidanylidene)-7-propan-2-yl-4~{H}-1$l^{6},2,4-benzothiadiazin-3-yl]amino]benzoic acid (3 entities in total) |
| Functional Keywords | dnph1, inhibitor, small molecule, drug discovery, ddr, dna damage response, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 35067.39 |
| Authors | |
| Primary citation | Barlaam, B.,Alonso-Crisostomo, L.,Anderson, N.A.,Argyrou, A.,Astles, P.C.,Cadogan, E.B.,Carlino, L.,Collie, G.W.,Davies, N.L.,Hall, J.,Kitching, L.,Li, X.,Michopoulos, F.,Milbradt, A.G.,Nikkila, J.,Northall, S.,O'Connor, M.J.,Pei, X.,Shaw, J.,Slade, D.,Southgate, H.,Stead, D.,Stubbs, C.J.,Whitehurst, B.C.,Xing, B.,Yuan, Y.,Zhou, J. Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2'-Deoxynucleoside 5'-Monophosphate Glycosidase (DNPH1). J.Med.Chem., 2025 Cited by PubMed 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 (binding affinity pIC 4.7), we identified compound as a very potent inhibitor of DNPH1 (pIC 9.3) using DNPH1 X-ray structure-guided drug design. Compound demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line. PubMed: 41194588DOI: 10.1021/acs.jmedchem.5c02356 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.489 Å) |
Structure validation
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