Development of a Series of Pyrrolopyridone MAT2A Inhibitors

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 (21), a potent inhibitor in vitro with ex...

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Published in:Journal of medicinal chemistry 2024-03, Vol.67 (6), p.4541-4559
Main Authors: Atkinson, Stephen J., Bagal, Sharan K., Argyrou, Argyrides, Askin, Sean, Cheung, Tony, Chiarparin, Elisabetta, Coen, Muireann, Collie, Iain T., Dale, Ian L., De Fusco, Claudia, Dillman, Keith, Evans, Laura, Feron, Lyman J., Foster, Alison J., Grondine, Michael, Kantae, Vasudev, Lamont, Gillian M., Lamont, Scott, Lynch, James T., Nilsson Lill, Sten, Robb, Graeme R., Saeh, Jamal, Schimpl, Marianne, Scott, James S., Smith, James, Srinivasan, Bharath, Tentarelli, Sharon, Vazquez-Chantada, Mercedes, Wagner, David, Walsh, Jarrod J., Watson, David, Williamson, Beth
Format: Article
Language:English
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Summary: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 (21), 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c01860