9RG8

Crystal structure of DNPH1 bound by compound 1.

This is a non-PDB format compatible entry.

Summary for 9RG8

• Entry DOI: 10.2210/pdb9rg8/pdb
• Descriptor: 5-hydroxymethyl-dUMP N-hydrolase, 2-[1-methyl-5-[[1-[3-(pyrimidin-2-ylamino)phenyl]carbonylpiperidin-4-yl]amino]-1,2,4-triazol-3-yl]-1~{H}-indole-6-carbonitrile (3 entities in total)
• Functional Keywords: dnph1, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 34867.16

Authors

Collie, G.W. (deposition date: 2025-06-05, release date: 2025-11-12, Last modification date: 2025-11-26)

Primary citation

Anderson, N.A.,Barlaam, B.,Argyrou, A.,Astles, P.C.,Bruss, H.,Cadogan, E.B.,Carlino, L.,Alonso-Crisostomo, L.,Collie, G.W.,Edwards, A.J.,Gryniukova, A.,Hall, J.,Jamal, K.,Kent, J.,Kitching, L.,Kourra, C.,Lam, C.,Milbradt, A.G.,Nikkila, J.,Northall, S.,O'Connor, M.J.,Overman, J.,Pathe, C.,Savory, W.,Slade, D.,Spencer, J.A.,Stead, D.,Stubbs, C.J.,Whitehurst, B.C.,Winfield, S.
Use of Direct-to-Biology Strategies for the Discovery of 2'-Deoxynucleoside 5'-Monophosphate N-Glycosidase (DNPH1) PROTACs.
J.Med.Chem., 68:23421-23447, 2025

PubMed Abstract: 2'-Deoxynucleoside 5'-monophosphate N-glycosidase (DNPH1) has emerged as an attractive target for cancer therapeutics exploiting DNA damage response pathways, yet chemical degraders for interrogating DNPH1 biology are lacking. We report the accelerated discovery of potent DNPH1 PROTACs using a direct-to-biology synthesis and screening platform. We employed miniaturized, array-based chemistry to generate a broad library of quinazoline-based PROTACs capable of recruiting a variety of different E3 ligases. Screening crude reaction mixtures in a cellular degradation assay enabled rapid identification of multiple nanomolar DNPH1 PROTACs, exemplified by compound , which achieved near-complete DNPH1 degradation and demonstrated strong functional activity in BRCA1 mutant cell lines. Mechanistic studies confirmed selective, proteasome- and VHL-dependent protein knockdown and recapitulation of phenotypic outcomes observed with DNPH1 genetic loss, including sensitization to hmdU treatment. Our findings highlight the power of D2B methodology to streamline PROTAC development and establish quinazoline-based degraders as robust chemical tools to advance DNPH1-targeted cancer research.

PubMed: 41183227
DOI: 10.1021/acs.jmedchem.5c02337

Experimental method

X-RAY DIFFRACTION (2.07 Å)