{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bielinski M"],"funding":["Innovative Medicines Initiative","European Federation of Pharmaceutical Industries and Associations","Cancer Research UK","Seventh Framework Programme","Wellcome Trust"],"pagination":["8227-8241"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11134331"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(21)"],"pubmed_abstract":["The three human SNM1 metallo-β-lactamase fold nucleases (SNM1A-C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site. Structure and turnover assay-guided optimization enabled the identification of potent quinazoline-hydroxamic acid containing inhibitors, which bind in a manner where the hydroxamic acid displaces the hydrolytic water and the quinazoline ring occupies a substrate nucleobase binding site. Cellular assays reveal that SNM1A inhibitors cause sensitisation to, and defects in the resolution of, cisplatin-induced DNA damage, validating the tractability of MBL fold nucleases as cancer drug targets."],"journal":["Chemical science"],"pubmed_title":["Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target."],"pmcid":["PMC11134331"],"funding_grant_id":["115489","A24759"],"pubmed_authors":["McElroy SP","Newman JA","Baddock HT","van Doornmalen E","Morrison A","Gileadi O","Jones PS","Schofield CJ","Henderson LR","Yosaatmadja Y","Bielinski M","van Groningen J","Swift LP","Brem J","Bowen MJ","van den Hurk H","van Boeckel S","McHugh PJ","Speake M"],"additional_accession":[]},"is_claimable":false,"name":"Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.","description":"The three human SNM1 metallo-β-lactamase fold nucleases (SNM1A-C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site. Structure and turnover assay-guided optimization enabled the identification of potent quinazoline-hydroxamic acid containing inhibitors, which bind in a manner where the hydroxamic acid displaces the hydrolytic water and the quinazoline ring occupies a substrate nucleobase binding site. Cellular assays reveal that SNM1A inhibitors cause sensitisation to, and defects in the resolution of, cisplatin-induced DNA damage, validating the tractability of MBL fold nucleases as cancer drug targets.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 May","modification":"2026-06-02T06:06:35.526Z","creation":"2026-04-15T03:09:52.271Z"},"accession":"S-EPMC11134331","cross_references":{"pubmed":["38817593"],"doi":["10.1039/d4sc00367e"]}}