Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

Robarge, Kirk D.; Lee, Wendy; Eigenbrot, Charles; Ultsch, Mark; Wiesmann, Christian; Heald, Robert; Price, Steve; Hewitt, Joanne; Jackson, Philip; Savy, Pascal; Burton, Brenda; Choo, Edna F.; Pang, Jodie; Boggs, Jason; Yang, April; Yang, Xioaye; Baumgardner, Matthew

doi:10.1016/j.bmcl.2014.08.008

Title: Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

Authors:: Robarge, Kirk D.; Lee, Wendy; Eigenbrot, Charles; Ultsch, Mark; Wiesmann, Christian; Heald, Robert; Price, Steve; Hewitt, Joanne; Jackson, Philip; Savy, Pascal; Burton, Brenda; Choo, Edna F.; Pang, Jodie; Boggs, Jason; Yang, April; Yang, Xioaye; Baumgardner, Matthew

Publication Date:: Wed Oct 01 00:00:00 EDT 2014

Sponsoring Org.:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

OSTI Identifier:: 1556516

Resource Type:: Publisher's Accepted Manuscript

Journal Name:: Bioorganic and Medicinal Chemistry Letters

Additional Journal Information:: Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Volume: 24 Journal Issue: 19; Journal ID: ISSN 0960-894X

Publisher:: Elsevier

Country of Publication:: United Kingdom

Language:: English

Citation Formats


                    Robarge, Kirk D., Lee, Wendy, Eigenbrot, Charles, Ultsch, Mark, Wiesmann, Christian, Heald, Robert, Price, Steve, Hewitt, Joanne, Jackson, Philip, Savy, Pascal, Burton, Brenda, Choo, Edna F., Pang, Jodie, Boggs, Jason, Yang, April, Yang, Xioaye, and Baumgardner, Matthew. Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479.  United Kingdom: N. p., 2014. 
Web.  doi:10.1016/j.bmcl.2014.08.008.

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                    Robarge, Kirk D., Lee, Wendy, Eigenbrot, Charles, Ultsch, Mark, Wiesmann, Christian, Heald, Robert, Price, Steve, Hewitt, Joanne, Jackson, Philip, Savy, Pascal, Burton, Brenda, Choo, Edna F., Pang, Jodie, Boggs, Jason, Yang, April, Yang, Xioaye, & Baumgardner, Matthew. Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479.  United Kingdom.  https://doi.org/10.1016/j.bmcl.2014.08.008

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                    Robarge, Kirk D., Lee, Wendy, Eigenbrot, Charles, Ultsch, Mark, Wiesmann, Christian, Heald, Robert, Price, Steve, Hewitt, Joanne, Jackson, Philip, Savy, Pascal, Burton, Brenda, Choo, Edna F., Pang, Jodie, Boggs, Jason, Yang, April, Yang, Xioaye, and Baumgardner, Matthew. Wed .  
"Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479".  United Kingdom.  https://doi.org/10.1016/j.bmcl.2014.08.008.

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@article{osti_1556516,

  title        = {Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479},

  author       = {Robarge, Kirk D. and Lee, Wendy and Eigenbrot, Charles and Ultsch, Mark and Wiesmann, Christian and Heald, Robert and Price, Steve and Hewitt, Joanne and Jackson, Philip and Savy, Pascal and Burton, Brenda and Choo, Edna F. and Pang, Jodie and Boggs, Jason and Yang, April and Yang, Xioaye and Baumgardner, Matthew},

  abstractNote = {},

  doi          = {10.1016/j.bmcl.2014.08.008},

  journal      = {Bioorganic and Medicinal Chemistry Letters},

  number       = 19,

  volume       = 24,

  place        = {United Kingdom},

  year         = {Wed Oct 01 00:00:00 EDT 2014},

  month        = {Wed Oct 01 00:00:00 EDT 2014}

}

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https://doi.org/10.1016/j.bmcl.2014.08.008

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Title: Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479

Citation Formats

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF journal, February 2010

The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition journal, March 2012

BRAF mutation predicts sensitivity to MEK inhibition journal, November 2005

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth journal, February 2010

Targeting RAS signalling pathways in cancer therapy journal, January 2003

Total Synthesis of Thiostrepton. Assembly of Key Building Blocks and Completion of the Synthesis journal, July 2005

The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer journal, January 2012

Predicting the Oxidative Metabolism of Statins: An Application of the MetaSite® Algorithm journal, January 2007

Medicinal Chemistry of hERG Optimizations: Highlights and Hang-Ups journal, August 2006

The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website journal, June 2004

Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers journal, August 2013

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations journal, November 2012

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition journal, November 2004

Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors journal, March 2009

Putative allosteric MEK1 and MEK2 inhibitors journal, May 2008

Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors journal, January 1999

Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions journal, May 2012

MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition journal, November 2013

Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF journal, January 2010

New combinations and immunotherapies for melanoma: latest evidence and clinical utility journal, August 2013

The RAF proteins take centre stage journal, November 2004

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
journal, February 2010

The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition
journal, March 2012

BRAF mutation predicts sensitivity to MEK inhibition
journal, November 2005

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
journal, February 2010

Targeting RAS signalling pathways in cancer therapy
journal, January 2003

Total Synthesis of Thiostrepton. Assembly of Key Building Blocks and Completion of the Synthesis
journal, July 2005

The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer
journal, January 2012

Predicting the Oxidative Metabolism of Statins: An Application of the MetaSite® Algorithm
journal, January 2007

Medicinal Chemistry of hERG Optimizations: Highlights and Hang-Ups
journal, August 2006

The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website
journal, June 2004

Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers
journal, August 2013

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations
journal, November 2012

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition
journal, November 2004

Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors
journal, March 2009

Putative allosteric MEK1 and MEK2 inhibitors
journal, May 2008

Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors
journal, January 1999

Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions
journal, May 2012

MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition
journal, November 2013

Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
journal, January 2010

New combinations and immunotherapies for melanoma: latest evidence and clinical utility
journal, August 2013

The RAF proteins take centre stage
journal, November 2004