posted on 2021-04-26, 17:34authored byClaudia 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.