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Development of a Series of Pyrrolopyridone MAT2A Inhibitors.
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.
Affiliation
  • Atkinson SJ; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Bagal SK; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Argyrou A; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Askin S; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Cheung T; Oncology R&D, AstraZeneca, R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • Chiarparin E; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Coen M; Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Collie IT; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Dale IL; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • De Fusco C; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Dillman K; Oncology R&D, AstraZeneca, R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • Evans L; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Feron LJ; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Foster AJ; Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Grondine M; Oncology R&D, AstraZeneca, R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • Kantae V; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Lamont GM; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Lamont S; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Lynch JT; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Nilsson Lill S; Data Sciences & Modelling, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg 431 83, Sweden.
  • Robb GR; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Saeh J; Oncology R&D, AstraZeneca, R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • Schimpl M; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Scott JS; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Smith J; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Srinivasan B; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Tentarelli S; Oncology R&D, AstraZeneca, R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • Vazquez-Chantada M; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Wagner D; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Walsh JJ; Discovery Sciences R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Watson D; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • Williamson B; Oncology R&D, AstraZeneca, The Discovery Centre, Cambridge Biomedical Campus, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
J Med Chem ; 67(6): 4541-4559, 2024 Mar 28.
Article in En | MEDLINE | ID: mdl-38466661
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neoplasms Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2024 Document type: Article Country of publication: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neoplasms Limits: Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2024 Document type: Article Country of publication: Estados Unidos