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Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.
Elsayed, Mohamed S A; Blake, James F; Boys, Mark L; Brown, Eric; Chapsal, Bruno D; Chicarelli, Mark J; Cook, Adam W; Fell, Jay B; Fischer, John P; Hanson, Lauren; Lemieux, Christine; Martinson, Matthew C; McCown, Joseph; McNulty, Oren T; Mejia, Macedonio J; Neitzel, Nickolas A; Otten, Jennifer N; Rodriguez, Martha E; Wilcox, Daniel; Wong, Christina E; Zhou, Yeyun; Hinklin, Ronald J.
Afiliación
  • Elsayed MSA; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Blake JF; Computational Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Boys ML; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Brown E; Pharmacology, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Chapsal BD; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Chicarelli MJ; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Cook AW; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Fell JB; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Fischer JP; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Hanson L; Enzymology, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Lemieux C; Cellular Biology, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Martinson MC; Enzymology, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • McCown J; ADME Sciences, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • McNulty OT; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Mejia MJ; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Neitzel NA; DMPK, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Otten JN; ADME Sciences, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Rodriguez ME; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Wilcox D; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Wong CE; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Zhou Y; Structural Biology, Pfizer-Boulder, Boulder, Colorado 80301, United States.
  • Hinklin RJ; Medicinal Chemistry, Pfizer-Boulder, Boulder, Colorado 80301, United States.
ACS Med Chem Lett ; 14(12): 1673-1681, 2023 Dec 14.
Article en En | MEDLINE | ID: mdl-38116446
ABSTRACT
SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors. Our efforts led to the discovery of the 5-azaquinoxaline as a new core for developing this class of compounds. Optimization of the potency and properties of this scaffold generated compound 30, that exhibited potent in vitro SHP2 inhibition and showed excellent in vivo efficacy and pharmacokinetic profile.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos