Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas
作者： Robert Roskoski
DOI: 10.1016/J.PHRS.2016.12.009
关键词:
摘要: The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events are involved in cell proliferation or the contrary of differentiation. Dysregulation this occurs more than one-third all malignancies, process has fostered development targeted Map kinase inhibitors. Cutaneous melanomas, which arise skin melanocytes, most aggressive form cancer. Mutations activate occur 90% these melanomas. This led to combination dabrafenib trametinib vemurafenib cobimetanib for treatment BRAF V600E mutant Dabrafenib target V600E/K mutants while MEK1/2. latter two agents bind MEK1/2 at site adjacent to, but separate from, ATP-binding therefore classified as type III allosteric protein These hydrogen bond with β3-lysine they make numerous hydrophobic contacts residues within αC-helix, β5 strand, activation segment, regions domain exhibit greater diversity those found site. One advantage such inhibitors do not have compete millimolar concentrations ATP, FDA-approved small molecule competitive imatinib must do. Owing wide spread neoplasms, cobimetinib being studied other cytotoxic drugs variety clinical situations. Except NRAS mutations, there no biomarkers correlated responses following inhibition discovery would represent an important therapeutic breakthrough.
sci-hub.se 参考文章(61)
Chao-Feng Zheng, Kun-Liang Guan, None, Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues The EMBO Journal. ,vol. 13, pp. 1123- 1131 ,(1994) , 10.1002/J.1460-2075.1994.TB06361.X
D.R. Alessi, Y. Saito, D.G. Campbell, P. Cohen, G. Sithanandam, U. Rapp, A. Ashworth, C.J. Marshall, S. Cowley, Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. The EMBO Journal. ,vol. 13, pp. 1610- 1619 ,(1994) , 10.1002/J.1460-2075.1994.TB06424.X
Christopher J. Caunt, Matthew J. Sale, Paul D. Smith, Simon J. Cook, MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road Nature Reviews Cancer. ,vol. 15, pp. 577- 592 ,(2015) , 10.1038/NRC4000
Steven K. Hanks, Tony Hunter, Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. The FASEB Journal. ,vol. 9, pp. 576- 596 ,(1995) , 10.1096/FASEBJ.9.8.7768349
Robert Roskoski, A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacological Research. ,vol. 100, pp. 1- 23 ,(2015) , 10.1016/J.PHRS.2015.07.010
Peng Wu, Mads H. Clausen, Thomas E. Nielsen, Allosteric small-molecule kinase inhibitors Pharmacology & Therapeutics. ,vol. 156, pp. 59- 68 ,(2015) , 10.1016/J.PHARMTHERA.2015.10.002
Robert Roskoski, Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacological Research. ,vol. 103, pp. 26- 48 ,(2016) , 10.1016/J.PHRS.2015.10.021
Rehan Akbani, KadiráC Akdemir, B áArman Aksoy, Monique Albert, Adrian Ally, SamirkumaráB Amin, Harindra Arachchi, Arshi Arora, J áTodd Auman, Brenda Ayala, Julien Baboud, Miruna Balasundaram, Saianand Balu, Nandita Barnabas, John Bartlett, Pam Bartlett, BorisáC Bastian, StephenáB Baylin, Madhusmita Behera, Dmitry Belyaev, Christopher Benz, Brady Bernard, Rameen Beroukhim, Natalie Bir, AaronáD Black, Tom Bodenheimer, Lori Boice, GenevieveáM Boland, Riccardo Bono, MoizáS Bootwalla, Marcus Bosenberg, Jay Bowen, Reanne Bowlby, ChristopheráA Bristow, Laura Brockway-Lunardi, Denise Brooks, Jakub Brzezinski, Wiam Bshara, Elizabeth Buda, WilliamáR Burns, YaronáS N Butterfield, Michael Button, Tiffany Calderone, GiancarloáAntonini Cappellini, Candace Carter, ScottáL Carter, Lynn Cherney, AndrewáD Cherniack, Aaron Chevalier, Lynda Chin, Juok Cho, RaymondáJ Cho, Yoon-La Choi, Andy Chu, Sudha Chudamani, Kristian Cibulskis, Giovanni Ciriello, Amanda Clarke, Stephen Coons, Leslie Cope, Daniel Crain, Erin Curley, Ludmila Danilova, Stefania D’Atri, Tanja Davidsen, MichaeláA Davies, KeitháA Delman, JohnáA Demchok, QixiaáA Deng, YonathanáLissanu Deribe, Noreen Dhalla, Rajiv Dhir, Daniel DiCara, Michael Dinikin, Michael Dubina, J áStephen Ebrom, Sophie Egea, Greg Eley, Jay Engel, JenniferáM Eschbacher, KonstantináV Fedosenko, Ina Felau, Timothy Fennell, MartináL Ferguson, Sheila Fisher, KeitháT Flaherty, Scott Frazer, Jessica Frick, Victoria Fulidou, StaceyáB Gabriel, Jianjiong Gao, Johanna Gardner, LeviáA Garraway, JulieáM Gastier-Foster, Carmelo Gaudioso, Nils Gehlenborg, Giannicola Genovese, Mark Gerken, JeffreyáE Gershenwald, Gad Getz, Carmen Gomez-Fernandez, Thomas Gribbin, Jonna Grimsby, Benjamin Gross, Ranabir Guin, Tony Gutschner, Angela Hadjipanayis, Ruth Halaban, Benjamin Hanf, David Haussler, LaurenáE Haydu, D áNeil Hayes, NicholasáK Hayward, DavidáI Heiman, Lynn Herbert, JamesáG Herman, Peter Hersey, KatherineáA Hoadley, Eran Hodis, RobertáA Holt, DaveáSB Hoon, Susan Hoppough, AlanáP Hoyle, FranklináW Huang, Mei Huang, Sharon Huang, CarolynáM Hutter, Matthew Ibbs, Lisa Iype, Anders Jacobsen, Valerie Jakrot, Alyssa Janning, WilliamáR Jeck, StuartáR Jefferys, MarkáA Jensen, CorbináD Jones, StevenáJ M Jones, Zhenlin Ju, Hojabr Kakavand, Hyojin Kang, RichardáF Kefford, FadloáR Khuri, Jaegil Kim, JohnáM Kirkwood, Joachim Klode, Anil Korkut, Konstanty Korski, Michael Krauthammer, Raju Kucherlapati, LawrenceáN Kwong, None, Genomic Classification of Cutaneous Melanoma Cell. ,vol. 161, pp. 1681- 1696 ,(2015) , 10.1016/J.CELL.2015.05.044
Susan S. Taylor, Alexandr P. Kornev, Protein kinases: evolution of dynamic regulatory proteins Trends in Biochemical Sciences. ,vol. 36, pp. 65- 77 ,(2011) , 10.1016/J.TIBS.2010.09.006
Yuliya Pylayeva-Gupta, Elda Grabocka, Dafna Bar-Sagi, RAS oncogenes: weaving a tumorigenic web Nature Reviews Cancer. ,vol. 11, pp. 761- 774 ,(2011) , 10.1038/NRC3106