Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers

Jongwon Lim; Elizabeth H Kelley; Joey L Methot; Hua Zhou; Alessia Petrocchi; Hongmin Chen; Susan E Hill; Marlene C Hinton; Alan Hruza; Joon O Jung; John K F Maclean; My Mansueto; George N Naumov; Ulrike Philippar; Shruti Raut; Peter Spacciapoli; Dongyu Sun; Phieng Siliphaivanh

doi:10.1021/acs.jmedchem.6b00708

Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers

J Med Chem. 2016 Jul 14;59(13):6501-11. doi: 10.1021/acs.jmedchem.6b00708. Epub 2016 Jul 1.

Authors

Jongwon Lim¹, Elizabeth H Kelley¹, Joey L Methot¹, Hua Zhou¹, Alessia Petrocchi¹, Hongmin Chen¹, Susan E Hill¹, Marlene C Hinton¹, Alan Hruza¹, Joon O Jung¹, John K F Maclean¹, My Mansueto¹, George N Naumov¹, Ulrike Philippar¹, Shruti Raut¹, Peter Spacciapoli¹, Dongyu Sun¹, Phieng Siliphaivanh¹

Affiliation

¹ Departments of †Chemistry, ‡Oncology, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Chemistry Modeling and Informatics, #Pharmacokinetics, Pharmacodynamics and Drug Metabolism, and ∇Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

PMID: 27329786
DOI: 10.1021/acs.jmedchem.6b00708

Abstract

The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAF(V600E) xenograft model.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
Mice
Models, Molecular
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / chemistry
Urea / pharmacology

Substances

1-(3-(2-methylpyridin-4-yl)-1H-pyrazolo(4,3-c)pyridin-6-yl)-3-(1-phenylethyl)urea
Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Urea
Extracellular Signal-Regulated MAP Kinases