Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.

Abstract

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.

• Authors: Erick J Morris, Sharda Jha, Clifford R Restaino, Priya Dayananth, Hugh Zhu, Alan Cooper, Donna Carr, Yongi Deng, Weihong Jin, Stuart Black, Brian Long, Jenny Liu, Edward Dinunzio, William Windsor, Rumin Zhang, Shuxia Zhao, Minilik H Angagaw, Elaine M Pinheiro, Jagdish Desai, Li Xiao, Gerald Shipps, Alan Hruza, James Wang, Joe Kelly, Sunil Paliwal, Xiaolei Gao, Boga Sobhana Babu, Liang Zhu, Pierre Daublain, Ling Zhang, Bart A Lutterbach, Marc R Pelletier, Ulrike Philippar, Phieng Siliphaivanh, David Witter, Paul Kirschmeier, W Robert Bishop, Daniel Hicklin, D Gary Gilliland, Lata Jayaraman, Leigh Zawel, Stephen Fawell, Ahmed A Samatar
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 7 Pg. 742-50 (Jul 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23614898 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase Kinases

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, genetics, metabolism)
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors, genetics)
• Mutation
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)