View source for 9rg8


==Crystal structure of DNPH1 bound by compound 1.==
<StructureSection load='9rg8' size='340' side='right'caption='[[9rg8]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9rg8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9RG8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9RG8 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.07&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JFX: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'>A1JFX</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9rg8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9rg8 OCA], [https://pdbe.org/9rg8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9rg8 RCSB], [https://www.ebi.ac.uk/pdbsum/9rg8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9rg8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DNPH1_HUMAN 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]
<div style="background-color:#fffaf0;">
== 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<ref>PMID:41183227</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9rg8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Collie GW]]