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

• Published in: Journal of medicinal chemistry 2021-05, Vol.64 (10), p.6814-6826
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00067

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.