Structural basis for the action of the drug trametinib at KSR-bound MEK

Khan, Zaigham M.; Real, Alexander M.; Marsiglia, William M.; Chow, Arthur; Duffy, Mary E.; Yerabolu, Jayasudhan R.; Scopton, Alex P.; Dar, Arvin C.

doi:10.1038/s41586-020-2760-4

Structural basis for the action of the drug trametinib at KSR-bound MEK

Journal Article · 21 December 2020 · Nature

DOI:https://doi.org/10.1038/s41586-020-2760-4· OSTI ID:1745045

Khan, Zaigham M.; Real, Alexander M.; Marsiglia, William M.; Chow, Arthur; Duffy, Mary E.; Yerabolu, Jayasudhan R.; Scopton, Alex P.; Dar, Arvin C. ^[1]

Icahn

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1745045

Journal Information:: Nature, Vol. 588, Issue 09, 2020

Country of Publication:: United States

Language:: ENGLISH

References (42)

The clinical development of MEK inhibitors Zhao, Yujie; Adjei, Alex A. Nature Reviews Clinical Oncology, Vol. 11, Issue 7 https://doi.org/10.1038/nrclinonc.2014.83	journal	May 2014
MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade Ebert, Peter J. R.; Cheung, Jeanne; Yang, Yagai Immunity, Vol. 44, Issue 3 https://doi.org/10.1016/j.immuni.2016.01.024	journal	March 2016
The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4 Liu, Li; Mayes, Patrick A.; Eastman, Stephen Clinical Cancer Research, Vol. 21, Issue 7 https://doi.org/10.1158/1078-0432.CCR-14-2339	journal	January 2015
The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity Slack, Cathy; Alic, Nazif; Foley, Andrea Cell, Vol. 162, Issue 1 https://doi.org/10.1016/j.cell.2015.06.023	journal	July 2015
Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral MAPK/ERK Kinase Inhibitor PD-0325901 in Patients with Advanced Cancers LoRusso, Patricia M.; Krishnamurthi, Smitha S.; Rinehart, John J. Clinical Cancer Research, Vol. 16, Issue 6 https://doi.org/10.1158/1078-0432.CCR-09-1883	journal	March 2010
PD0325901, a Mitogen-Activated Protein Kinase Kinase Inhibitor, Produces Ocular Toxicity in a Rabbit Animal Model of Retinal Vein Occlusion Huang, Wenhu; Yang, Amy H.; Matsumoto, Diane Journal of Ocular Pharmacology and Therapeutics, Vol. 25, Issue 6 https://doi.org/10.1089/jop.2009.0060	journal	December 2009
MEK1 mutations confer resistance to MEK and B-RAF inhibition Emery, C. M.; Vijayendran, K. G.; Zipser, M. C. Proceedings of the National Academy of Sciences, Vol. 106, Issue 48 https://doi.org/10.1073/pnas.0905833106	journal	November 2009
Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors Lito, Piro; Saborowski, Anna; Yue, Jingyin Cancer Cell, Vol. 25, Issue 5 https://doi.org/10.1016/j.ccr.2014.03.011	journal	May 2014
V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer Gao, Yijun; Maria, Ann; Na, Na Cancer Discovery, Vol. 9, Issue 9 https://doi.org/10.1158/2159-8290.CD-19-0356	journal	June 2019
RAS Proteins and Their Regulators in Human Disease Simanshu, Dhirendra K.; Nissley, Dwight V.; McCormick, Frank Cell, Vol. 170, Issue 1 https://doi.org/10.1016/j.cell.2017.06.009	journal	June 2017
RAS-targeted therapies: is the undruggable drugged? Moore, Amanda R.; Rosenberg, Scott C.; McCormick, Frank Nature Reviews Drug Discovery, Vol. 19, Issue 8 https://doi.org/10.1038/s41573-020-0068-6	journal	June 2020
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial Long, Georgina V.; Stroyakovskiy, Daniil; Gogas, Helen The Lancet, Vol. 386, Issue 9992 https://doi.org/10.1016/S0140-6736(15)60898-4	journal	August 2015
Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers Kinsey, Conan G.; Camolotto, Soledad A.; Boespflug, Amelie M. Nature Medicine, Vol. 25, Issue 4 https://doi.org/10.1038/s41591-019-0367-9	journal	March 2019
The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity Canon, Jude; Rex, Karen; Saiki, Anne Y. Nature, Vol. 575, Issue 7781 https://doi.org/10.1038/s41586-019-1694-1	journal	October 2019
Identification of JTP-70902, a p15 ^INK4b -inductive compound, as a novel MEK1/2 inhibitor Yamaguchi, Takayuki; Yoshida, Takayuki; Kurachi, Reina Cancer Science, Vol. 98, Issue 11 https://doi.org/10.1111/j.1349-7006.2007.00604.x	journal	November 2007
How Structural Biologists and the Protein Data Bank Contributed to Recent FDA New Drug Approvals Westbrook, John D.; Burley, Stephen K. Structure, Vol. 27, Issue 2 https://doi.org/10.1016/j.str.2018.11.007	journal	February 2019
Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors Fischmann, Thierry O.; Smith, Catherine K.; Mayhood, Todd W. Biochemistry, Vol. 48, Issue 12 https://doi.org/10.1021/bi801898e	journal	March 2009
Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition Ohren, Jeffrey F.; Chen, Huifen; Pavlovsky, Alexander Nature Structural & Molecular Biology, Vol. 11, Issue 12 https://doi.org/10.1038/nsmb859	journal	November 2004
Identification and Characterization of a Novel Chemotype MEK Inhibitor Able to Alter the Phosphorylation State of MEK1/2 Yoshida, Takayuki; Kakegawa, Junya; Yamaguchi, Takayuki Oncotarget, Vol. 3, Issue 12 https://doi.org/10.18632/oncotarget.747	journal	December 2012
Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers Hatzivassiliou, Georgia; Haling, Jacob R.; Chen, Huifen Nature, Vol. 501, Issue 7466 https://doi.org/10.1038/nature12441	journal	August 2013
The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans Kornfeld, Kerry; Hom, Dennis B.; Horvitz, H. Robert Cell, Vol. 83, Issue 6 https://doi.org/10.1016/0092-8674(95)90206-6	journal	December 1995
Quantitative, Real-Time Measurements of Intracellular Target Engagement Using Energy Transfer Robers, Matthew B.; Vasta, James D.; Corona, Cesear R. Methods in Molecular Biology https://doi.org/10.1007/978-1-4939-8891-4_3	book	December 2018
Enhanced Inhibition of ERK Signaling by a Novel Allosteric MEK Inhibitor, CH5126766, That Suppresses Feedback Reactivation of RAF Activity Ishii, Nobuya; Harada, Naoki; Joseph, Eric W. Cancer Research, Vol. 73, Issue 13 https://doi.org/10.1158/0008-5472.CAN-12-3937	journal	May 2013
Long-lasting target binding and rebinding as mechanisms to prolong in vivo drug action: Drug-target binding and rebinding Vauquelin, Georges; Charlton, Steven J. British Journal of Pharmacology, Vol. 161, Issue 3 https://doi.org/10.1111/j.1476-5381.2010.00936.x	journal	September 2010
Regulation of RAF protein kinases in ERK signalling Lavoie, Hugo; Therrien, Marc Nature Reviews Molecular Cell Biology, Vol. 16, Issue 5 https://doi.org/10.1038/nrm3979	journal	April 2015
A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK Brennan, Damian F.; Dar, Arvin C.; Hertz, Nicholas T. Nature, Vol. 472, Issue 7343 https://doi.org/10.1038/nature09860	journal	March 2011
Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling Dhawan, Neil S.; Scopton, Alex P.; Dar, Arvin C. Nature, Vol. 537, Issue 7618 https://doi.org/10.1038/nature19327	journal	August 2016
Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling Haling, Jacob R.; Sudhamsu, Jawahar; Yen, Ivana Cancer Cell, Vol. 26, Issue 3 https://doi.org/10.1016/j.ccr.2014.07.007	journal	September 2014
Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization Liau, Nicholas P. D.; Wendorff, Timothy J.; Quinn, John G. Nature Structural & Molecular Biology, Vol. 27, Issue 2 https://doi.org/10.1038/s41594-019-0365-0	journal	January 2020
The drug–target residence time model: a 10-year retrospective Copeland, Robert A. Nature Reviews Drug Discovery, Vol. 15, Issue 2 https://doi.org/10.1038/nrd.2015.18	journal	December 2015
GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition Gilmartin, Aidan G.; Bleam, Maureen R.; Groy, Arthur Clinical Cancer Research, Vol. 17, Issue 5 https://doi.org/10.1158/1078-0432.CCR-10-2200	journal	January 2011
Targeting Alterations in the RAF–MEK Pathway Yaeger, Rona; Corcoran, Ryan B. Cancer Discovery, Vol. 9, Issue 3 https://doi.org/10.1158/2159-8290.CD-18-1321	journal	February 2019
Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors Sos, Martin L.; Levin, Rebecca S.; Gordan, John D. Cell Reports, Vol. 8, Issue 4 https://doi.org/10.1016/j.celrep.2014.07.010	journal	August 2014
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
electronic Ligand Builder and Optimization Workbench ( eLBOW ): a tool for ligand coordinate and restraint generation Moriarty, Nigel W.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 10 https://doi.org/10.1107/S0907444909029436	journal	September 2009
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement Vasta, James D.; Corona, Cesear R.; Wilkinson, Jennifer Cell Chemical Biology, Vol. 25, Issue 2 https://doi.org/10.1016/j.chembiol.2017.10.010	journal	February 2018
SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling Strub, Thomas; Ghiraldini, Flavia G.; Carcamo, Saul Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-05966-z	journal	August 2018
A dimerization-dependent mechanism drives RAF catalytic activation Rajakulendran, Thanashan; Sahmi, Malha; Lefrançois, Martin Nature, Vol. 461, Issue 7263 https://doi.org/10.1038/nature08314	journal	September 2009
MEK drives BRAF activation through allosteric control of KSR proteins Lavoie, Hugo; Sahmi, Malha; Maisonneuve, Pierre Nature, Vol. 554, Issue 7693 https://doi.org/10.1038/nature25478	journal	February 2018

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