Discovery of Highly Potent, Selective, and Efficacious Small Molecule Inhibitors of ERK1/2

Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Journal of medicinal chemistry 2015-02, Vol.58 (4), p.1976-1991
Hauptverfasser:	Ren, Li, Grina, Jonas, Moreno, David, Blake, James F, Gaudino, John J, Garrey, Rustam, Metcalf, Andrew T, Burkard, Michael, Martinson, Matthew, Rasor, Kevin, Chen, Huifen, Dean, Brian, Gould, Stephen E, Pacheco, Patricia, Shahidi-Latham, Sheerin, Yin, Jianping, West, Kristina, Wang, Weiru, Moffat, John G, Schwarz, Jacob B
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Proliferation - drug effects Crystallography, X-Ray Disease Models, Animal Dose-Response Relationship, Drug Drug Discovery Mice Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Models, Molecular Molecular Conformation Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyridones - administration & dosage Pyridones - chemistry Pyridones - pharmacology Rats Small Molecule Libraries - administration & dosage Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship Xenograft Model Antitumor Assays
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm501921k