2. Academic Validation
  3. Development of a Series of Pyrrolopyridone MAT2A Inhibitors

Development of a Series of Pyrrolopyridone MAT2A Inhibitors

  • J Med Chem. 2024 Mar 28;67(6):4541-4559. doi: 10.1021/acs.jmedchem.3c01860.
Stephen J Atkinson 1,  Sharan K Bagal 1,  Argyrides Argyrou 2,  Sean Askin 3,  Tony Cheung 4,  Elisabetta Chiarparin 1,  Muireann Coen 5,  Iain T Collie 2,  Ian L Dale 2,  Claudia De Fusco 2,  Keith Dillman 4,  Laura Evans 1,  Lyman J Feron 1,  Alison J Foster 5,  Michael Grondine 4,  Vasudev Kantae 2,  Gillian M Lamont 1,  Scott Lamont 1,  James T Lynch 1,  Sten Nilsson Lill 6,  Graeme R Robb 1,  Jamal Saeh 4,  Marianne Schimpl 2,  James S Scott 1,  James Smith 1,  Bharath Srinivasan 2,  Sharon Tentarelli 4,  Mercedes Vazquez-Chantada 2,  David Wagner 1,  Jarrod J Walsh 2,  David Watson 1,  Beth Williamson 1
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • 2 Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • 3 Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • 4 Oncology R&D, AstraZeneca, R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 5 Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • 6 Data Sciences & Modelling, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg 431 83, Sweden.
PMID: 38466661 DOI: 10.1021/acs.jmedchem.3c01860
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 (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.

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