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De Fusco, Claudia; Schimpl, Marianne; Börjesson, Ulf; Cheung, Tony; Collie, Iain; Evans, Laura; Narasimhan, Priyanka; Stubbs, Christopher; Vazquez-Chantada, Mercedes; Wagner, David J; Grondine, Michael; Sanders, Matthew G; Tentarelli, Sharon; Underwood, Elizabeth; Argyrou, Argyrides; Smith, James M; Lynch, James T; Chiarparin, Elisabetta; Robb, Graeme; Bagal, Sharan K; Scott, James S
Journal of medicinal chemistry, 05/2021, Letnik: 64, Številka: 10Journal Article
MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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