7bhs
Crystal structure of MAT2a with quinazoline fragment 2 bound in the allosteric siteCrystal structure of MAT2a with quinazoline fragment 2 bound in the allosteric site
Structural highlights
Function[METK2_HUMAN] Catalyzes the formation of S-adenosylmethionine from methionine and ATP. Publication Abstract from PubMedMAT2a 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. Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model.,De Fusco C, Schimpl M, Borjesson U, Cheung T, Collie I, Evans L, Narasimhan P, Stubbs C, Vazquez-Chantada M, Wagner DJ, Grondine M, Sanders MG, Tentarelli S, Underwood E, Argyrou A, Smith JM, Lynch JT, Chiarparin E, Robb G, Bagal SK, Scott JS J Med Chem. 2021 Apr 26. doi: 10.1021/acs.jmedchem.1c00067. PMID:33900758[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Human
- Large Structures
- Methionine adenosyltransferase
- Argyrou, A
- Bagal, S
- Borjesson, U
- Cheung, T
- Chiarparin, E
- Collie, I
- Evans, L
- Fusco, C De
- Grondine, M
- Narasimhan, P
- Robb, G
- Schimpl, M
- Scott, J S
- Stubbs, C
- Tentarelli, S
- Underwood, E
- Vazquez-Chantada, M
- Wagner, D J
- Allosteric inhibitor
- Fragment-based drug design
- Oncology
- Synthetic lethal therapy
- Transferase