9rg8

Crystal structure of DNPH1 bound by compound 1.

spinqualitylabelsall models 9rg8, resolution 2.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9rg8 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.07Å Ligands: A1JFX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DNPH1_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 PubMed 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 59, 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. Use of Direct-to-Biology Strategies for the Discovery of 2'-Deoxynucleoside 5'-Monophosphate N-Glycosidase (DNPH1) PROTACs.,Anderson NA, Barlaam B, Argyrou A, Astles PC, Bruss H, Cadogan EB, Carlino L, Alonso-Crisostomo L, Collie GW, Edwards AJ, Gryniukova A, Hall J, Jamal K, Kent J, Kitching L, Kourra C, Lam C, Milbradt AG, Nikkila J, Northall S, O'Connor MJ, Overman J, Pathe C, Savory W, Slade D, Spencer JA, Stead D, Stubbs CJ, Whitehurst BC, Winfield S J Med Chem. 2025 Nov 3. doi: 10.1021/acs.jmedchem.5c02337. PMID:41183227 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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