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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6501-6511
• 全文大小：500K
• 年卷期：0
• ISSN：1520-4804

文摘

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.