8QDZ

Crystal structure of human MAT2a bound to S-Adenosylmethionine and Compound 11

Summary for 8QDZ

• Entry DOI: 10.2210/pdb8qdz/pdb
• Descriptor: S-adenosylmethionine synthase isoform type-2, 3-cyclopropyl-4-(4-methoxyphenyl)-5-oxidanyl-pyrazolo[4,3-c]pyridine, S-ADENOSYLMETHIONINE, ... (4 entities in total)
• Functional Keywords: s-adenosylmethionine biosynthesis, allosteric inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 44615.57

Authors

Schimpl, M. (deposition date: 2023-08-30, release date: 2024-03-20, Last modification date: 2024-04-10)

Primary citation

Atkinson, S.J.,Bagal, S.K.,Argyrou, A.,Askin, S.,Cheung, T.,Chiarparin, E.,Coen, M.,Collie, I.T.,Dale, I.L.,De Fusco, C.,Dillman, K.,Evans, L.,Feron, L.J.,Foster, A.J.,Grondine, M.,Kantae, V.,Lamont, G.M.,Lamont, S.,Lynch, J.T.,Nilsson Lill, S.,Robb, G.R.,Saeh, J.,Schimpl, M.,Scott, J.S.,Smith, J.,Srinivasan, B.,Tentarelli, S.,Vazquez-Chantada, M.,Wagner, D.,Walsh, J.J.,Watson, D.,Williamson, B.
Development of a Series of Pyrrolopyridone MAT2A Inhibitors.
J.Med.Chem., 67:4541-4559, 2024

PubMed Abstract: The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

PubMed: 38466661
DOI: 10.1021/acs.jmedchem.3c01860

Experimental method

X-RAY DIFFRACTION (1.16 Å)