9I6E

Crystal structure of DNPH1 bound by compound 5.

これはPDB形式変換不可エントリーです。

9I6E の概要

• エントリーDOI: 10.2210/pdb9i6e/pdb
• 分子名称: 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)
• 機能のキーワード: dnph1, inhibitor, small molecule, drug discovery, ddr, dna damage response, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35067.39

構造登録者

Collie, G.W. (登録日: 2025-01-29, 公開日: 2025-11-12, 最終更新日: 2025-12-10)

主引用文献

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., 68:24381-24403, 2025

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: 41194588
DOI: 10.1021/acs.jmedchem.5c02356

実験手法

X-RAY DIFFRACTION (1.489 Å)