5KE0

Discovery of 1-1H-Pyrazolo 4,3-c pyridine-6-yl urea Inhibitors of Extracellular Signal Regulated Kinase ERK for the Treatment of Cancers

Summary for 5KE0

• Entry DOI: 10.2210/pdb5ke0/pdb
• Descriptor: Mitogen-activated protein kinase 1, 1-[3-(2-methylpyridin-4-yl)-1~{H}-pyrazolo[4,3-c]pyridin-6-yl]-3-(phenylmethyl)urea, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transferase, serine/threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (Rat)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P63086
• Total number of polymer chains: 1
• Total formula weight: 43200.42

Authors

Hruza, A.,Lim, J. (deposition date: 2016-06-09, release date: 2016-07-06, Last modification date: 2024-03-06)

Primary citation

Lim, J.,Kelley, E.H.,Methot, J.L.,Zhou, H.,Petrocchi, A.,Chen, H.,Hill, S.E.,Hinton, M.C.,Hruza, A.,Jung, J.O.,Maclean, J.K.,Mansueto, M.,Naumov, G.N.,Philippar, U.,Raut, S.,Spacciapoli, P.,Sun, D.,Siliphaivanh, P.
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., 59:6501-6511, 2016

PubMed 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.

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

Experimental method

X-RAY DIFFRACTION (1.68 Å)