期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 10, 页码 6814-6826出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00067
关键词
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MAT2a is an enzyme that synthesizes the essential metabolite SAM, making it an attractive target for treating MTAP-deleted cancers sensitive to its inhibition. Through structure-guided design and systematic SAR exploration, a potent series of MAT2a inhibitors has been developed, demonstrating promising antitumor response in in vivo studies.
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.
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