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

Journal of medicinal chemistry (2021-04-27)
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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
McCoy 5A培养基, Modified, with sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
牛血清白蛋白 来源于牛血清, heat shock fraction, pH 5.2, ≥96%