Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2′-Deoxynucleoside 5′-Monophosphate Glycosidase (DNPH1)

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 1 (binding affinity pIC50 4.7), we identified compound 38 as a very potent inhibitor of DNPH1 (pIC50 9.3) using DNPH1 X-ray structure-guided drug design. Compound 38 demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC50 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line.

DNPH1是一种核苷酸池净化剂，可裂解5-羟甲基-2-脱氧尿苷-5-单磷酸（5-hydroxymethyl-2-deoxyuridine-5-monophosphate，hmdUMP），阻止对应非天然核苷酸掺入DNA。近期研究表明，DNPH1缺失可增强同源重组修复（HRR）缺陷型癌症对聚腺苷二磷酸核糖聚合酶（PARP）抑制剂的敏感性。本研究报道了一类非核苷类DNPH1抑制剂的优化历程：从结合亲和力pIC50为4.7的弱活性化合物1出发，依托DNPH1 X射线晶体结构指导的药物设计策略，筛选得到活性极强的DNPH1抑制剂化合物38（pIC50=9.3）。化合物38在SUM149PT细胞系中可实现对DNPH1的靶点结合（pIC50=7.2）。以此工具化合物为研究对象，本研究进一步报道了DNPH1抑制剂在BRCA1突变型SUM149PT细胞系中的体外药理学特性。