42026-56-2Relevant academic research and scientific papers
Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model
De Fusco, Claudia,Schimpl, Marianne,B?rjesson, 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.
, p. 6814 - 6826 (2021)
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.
