biostudies-literatureBielinski MInnovative Medicines InitiativeEuropean Federation of Pharmaceutical Industries and AssociationsCancer Research UKSeventh Framework ProgrammeWellcome Trust8227-8241https://www.ebi.ac.uk/biostudies/studies/S-EPMC11134331biostudies-literatureUnknown15(21)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.Chemical scienceCell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.PMC11134331115489A24759McElroy SPNewman JABaddock HTvan Doornmalen EMorrison AGileadi OJones PSSchofield CJHenderson LRYosaatmadja YBielinski Mvan Groningen JSwift LPBrem JBowen MJvan den Hurk Hvan Boeckel SMcHugh PJSpeake MfalseCell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.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.2024-01-01T00:00:00Z2024 May2026-06-02T06:06:35.526Z2026-04-15T03:09:52.271ZS-EPMC111343313881759310.1039/d4sc00367e