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Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent.
Foote, Kevin M; Nissink, J Willem M; McGuire, Thomas; Turner, Paul; Guichard, Sylvie; Yates, James W T; Lau, Alan; Blades, Kevin; Heathcote, Dan; Odedra, Rajesh; Wilkinson, Gary; Wilson, Zena; Wood, Christine M; Jewsbury, Philip J.
Afiliación
  • Foote KM; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • Nissink JWM; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • McGuire T; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • Turner P; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • Guichard S; Bioscience, Oncology, IMED Biotech Unit , AstraZeneca , Chesterford Research Park , Little Chesterford, Cambridge CB10 1XL , U.K.
  • Yates JWT; DMPK, Oncology, IMED Biotech Unit , AstraZeneca , Chesterford Research Park , Little Chesterford, Cambridge CB10 1XL , U.K.
  • Lau A; Bioscience, Oncology, IMED Biotech Unit , AstraZeneca , Chesterford Research Park , Little Chesterford, Cambridge CB10 1XL , U.K.
  • Blades K; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • Heathcote D; Discovery Sciences, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • Odedra R; Bioscience, Oncology, IMED Biotech Unit , AstraZeneca , Chesterford Research Park , Little Chesterford, Cambridge CB10 1XL , U.K.
  • Wilkinson G; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • Wilson Z; Bioscience, Oncology, IMED Biotech Unit , AstraZeneca , Chesterford Research Park , Little Chesterford, Cambridge CB10 1XL , U.K.
  • Wood CM; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
  • Jewsbury PJ; Chemistry, Oncology, IMED Biotech Unit , AstraZeneca , Cambridge Science Park, 310 Milton Road , Milton, Cambridge CB4 0WG , U.K.
J Med Chem ; 61(22): 9889-9907, 2018 11 21.
Article en En | MEDLINE | ID: mdl-30346772
The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Sulfóxidos / Inhibidores de Proteínas Quinasas / Descubrimiento de Drogas / Proteínas de la Ataxia Telangiectasia Mutada / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirimidinas / Sulfóxidos / Inhibidores de Proteínas Quinasas / Descubrimiento de Drogas / Proteínas de la Ataxia Telangiectasia Mutada / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos