7BHS

Crystal structure of MAT2a with quinazoline fragment 2 bound in the allosteric site

Summary for 7BHS

• Entry DOI: 10.2210/pdb7bhs/pdb
• Descriptor: S-adenosylmethionine synthase isoform type-2, 6-chloranyl-2-methoxy-4-phenyl-quinazoline, S-ADENOSYLMETHIONINE, ... (4 entities in total)
• Functional Keywords: allosteric inhibitor, fragment-based drug design, synthetic lethal therapy, oncology, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44604.98

Authors

Schimpl, M.,De Fusco, C.,Borjesson, U.,Cheung, T.,Collie, I.,Evans, L.,Narasimhan, P.,Stubbs, C.,Vazquez-Chantada, M.,Wagner, D.J.,Grondine, M.,Tentarelli, S.,Underwood, E.,Argyrou, A.,Bagal, S.,Chiarparin, E.,Robb, G.,Scott, J.S. (deposition date: 2021-01-11, release date: 2021-04-21, Last modification date: 2024-05-01)

Primary citation

De Fusco, C.,Schimpl, M.,Borjesson, U.,Cheung, T.,Collie, I.,Evans, L.,Narasimhan, P.,Stubbs, C.,Vazquez-Chantada, M.,Wagner, D.J.,Grondine, M.,Sanders, M.G.,Tentarelli, S.,Underwood, E.,Argyrou, A.,Smith, J.M.,Lynch, J.T.,Chiarparin, E.,Robb, G.,Bagal, S.K.,Scott, J.S.
Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model.
J.Med.Chem., 64:6814-6826, 2021

PubMed Abstract: MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite -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 tool compound reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells . studies showed that was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

PubMed: 33900758
DOI: 10.1021/acs.jmedchem.1c00067

Experimental method

X-RAY DIFFRACTION (1.05 Å)