9RPO

Crystal structure of DNPH1 bound by compound 3

This is a non-PDB format compatible entry.

Summary for 9RPO

• Entry DOI: 10.2210/pdb9rpo/pdb
• Descriptor: 5-hydroxymethyl-dUMP N-hydrolase, 1-[4-[[(2~{E})-2-(4-chloranylcyclohexa-2,4-dien-1-ylidene)-1,3-dihydroimidazol-4-yl]carbonyl]piperazin-1-yl]-2,2-dimethyl-propan-1-one (3 entities in total)
• Functional Keywords: dna damage response, inhibitor, drug discovery, cancer, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 35102.35

Authors

Collie, G.W. (deposition date: 2025-06-25, release date: 2025-12-24, Last modification date: 2026-01-28)

Primary citation

Whitehurst, B.C.,Anderson, N.A.,Argyrou, A.,Astles, P.,Barlaam, B.,Cadogan, E.B.,Carlino, L.,Collie, G.W.,Edwards, A.,Kitching, L.,Li, Y.,Milbradt, A.G.,Nikkila, J.,Northall, S.,Pahlen, S.,Patel, S.,Savory, W.,Schade, M.,Spencer, J.A.,Stead, D.,Stubbs, C.J.,Wang, A.,Wang, W.
Discovery and Characterization of Diverse Non-nucleotide Inhibitors of DNPH1 Using an Integrated Hit Finding Strategy.
Acs Med.Chem.Lett., 17:226-234, 2026

PubMed Abstract: DNPH1 is a hydrolase enzyme that degrades the noncanonical nucleotide 5-hydroxymethyl-2'-deoxyuridine 5'-monophosphate (hmdUMP), thus acting as a nucleotide pool sanitizer by preventing its aberrant incorporation into DNA. Recent studies have shown that loss of DNPH1 enhances the sensitivity of homologous recombination repair-deficient cancer cells to PARP inhibitors, highlighting its potential as an attractive therapeutic target. Herein we report the design and prosecution of an integrated hit finding strategy combining high-throughput screening, DNA-encoded library screening, and fragment-based lead generation which enabled the discovery of the first non-nucleotide ligands for DNPH1. We compare four hit compounds which differ markedly in their chemical structures, physicochemical properties, and binding modes and summarize parallel hit-to-lead workup efforts. We also provide discussion of the merits of an integrated approach for hit discovery when applied to challenging novel targets such as DNPH1.

PubMed: 41531952
DOI: 10.1021/acsmedchemlett.5c00651

Experimental method

X-RAY DIFFRACTION (2.019 Å)