1.
J Med Chem
; 58(4): 1976-91, 2015 Feb 26.
Article
in English
| MEDLINE
| ID: mdl-25603482
ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Protein Kinase Inhibitors/pharmacology , Pyridones/pharmacology , Small Molecule Libraries/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Crystallography, X-Ray , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Mice , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyridones/administration & dosage , Pyridones/chemistry , Rats , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor Assays
2.
Bioorg Med Chem Lett
; 24(12): 2635-9, 2014 Jun 15.
Article
in English
| MEDLINE
| ID: mdl-24813737
ABSTRACT
The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.
