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Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model

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journal contribution
posted on 26.04.2021, 17:34 by Claudia De Fusco, Marianne Schimpl, Ulf Börjesson, Tony Cheung, Iain Collie, Laura Evans, Priyanka Narasimhan, Christopher Stubbs, Mercedes Vazquez-Chantada, David J. Wagner, Michael Grondine, Matthew G. Sanders, Sharon Tentarelli, Elizabeth Underwood, Argyrides Argyrou, James M. Smith, James T. Lynch, Elisabetta Chiarparin, Graeme Robb, Sharan K. Bagal, James S. Scott
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.