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...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 58; no. 4; pp. 1976 - 1991
Main Authors 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 Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 26.02.2015
Amer Chemical Soc
Subjects
Administration, Oral
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Chemistry, Medicinal
Crystallography, X-Ray
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Discovery
Life Sciences & Biomedicine
Mice
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Models, Molecular
Molecular Conformation
Pharmacology & Pharmacy
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyridones - administration & dosage
Pyridones - chemistry
Pyridones - pharmacology
Rats
Science & Technology
Small Molecule Libraries - administration & dosage
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
Xenograft Model Antitumor Assays
ACQUIRED-RESISTANCE
BRAF
PATHWAY
KINASES
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501921k