1s9i Citations

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.


MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.

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Reviews citing this publication (68)

  1. Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges. Millet A, Martin AR, Ronco C, Rocchi S, Benhida R. Med Res Rev 37 98-148 (2017)
  2. ETS-targeted therapy: can it substitute for MEK inhibitors? Tetsu O, McCormick F. Clin Transl Med 6 16 (2017)
  3. Emerging Computational Methods for the Rational Discovery of Allosteric Drugs. Wagner JR, Lee CT, Durrant JD, Malmstrom RD, Feher VA, Amaro RE. Chem. Rev. 116 6370-6390 (2016)
  4. ERK1 and ERK2 Map Kinases: Specific Roles or Functional Redundancy? Buscà R, Pouysségur J, Lenormand P. Front Cell Dev Biol 4 53 (2016)
  5. Allosteric modulators of MEK1: drug design and discovery. Shang J, Lu S, Jiang Y, Zhang J. Chem Biol Drug Des 88 485-497 (2016)
  6. Ten things you should know about protein kinases: IUPHAR Review 14. Fabbro D, Cowan-Jacob SW, Moebitz H. Br. J. Pharmacol. 172 2675-2700 (2015)
  7. MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms. Wu PK, Park JI. Semin. Oncol. 42 849-862 (2015)
  8. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Caunt CJ, Sale MJ, Smith PD, Cook SJ. Nat. Rev. Cancer 15 577-592 (2015)
  9. Recent progress on MAP kinase pathway inhibitors. Uehling DE, Harris PA. Bioorg. Med. Chem. Lett. 25 4047-4056 (2015)
  10. BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Richman J, Martin-Liberal J, Diem S, Larkin J. Expert Opin Pharmacother 16 1285-1297 (2015)
  11. Multiple café au lait spots in familial patients with MAP2K2 mutation. Takenouchi T, Shimizu A, Torii C, Kosaki R, Takahashi T, Saya H, Kosaki K. Am. J. Med. Genet. A 164A 392-396 (2014)
  12. MAP kinase modules: the excursion model and the steps that count. Piala AT, Humphreys JM, Goldsmith EJ. Biophys. J. 107 2006-2015 (2014)
  13. The biology and clinical development of MEK inhibitors for cancer. Luke JJ, Ott PA, Shapiro GI. Drugs 74 2111-2128 (2014)
  14. Intrinsic and acquired resistance to MEK1/2 inhibitors in cancer. Sale MJ, Cook SJ. Biochem. Soc. Trans. 42 776-783 (2014)
  15. Composition and applications of focus libraries to phenotypic assays. Wassermann AM, Camargo LM, Auld DS. Front Pharmacol 5 164 (2014)
  16. The clinical development of MEK inhibitors. Zhao Y, Adjei AA. Nat Rev Clin Oncol 11 385-400 (2014)
  17. Harnessing allostery: a novel approach to drug discovery. Lu S, Li S, Zhang J. Med Res Rev 34 1242-1285 (2014)
  18. Exploration of type II binding mode: A privileged approach for kinase inhibitor focused drug discovery? Zhao Z, Wu H, Wang L, Liu Y, Knapp S, Liu Q, Gray NS. ACS Chem. Biol. 9 1230-1241 (2014)
  19. Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Little AS, Smith PD, Cook SJ. Oncogene 32 1207-1215 (2013)
  20. ATP-noncompetitive CDK inhibitors for cancer therapy: an overview. Abate AA, Pentimalli F, Esposito L, Giordano A. Expert Opin Investig Drugs 22 895-906 (2013)
  21. αC helix displacement as a general approach for allosteric modulation of protein kinases. Palmieri L, Rastelli G. Drug Discov. Today 18 407-414 (2013)
  22. A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets. Uitdehaag JC, Verkaar F, Alwan H, de Man J, Buijsman RC, Zaman GJ. Br. J. Pharmacol. 166 858-876 (2012)
  23. Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma. Kudo M. World J. Gastroenterol. 18 6005-6017 (2012)
  24. Autoregulation of kinase dephosphorylation by ATP binding in AGC protein kinases. Chan TO, Pascal JM, Armen RS, Rodeck U. Cell Cycle 11 475-478 (2012)
  25. KRAS and BRAF: drug targets and predictive biomarkers. Vakiani E, Solit DB. J. Pathol. 223 219-229 (2011)
  26. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Dar AC, Shokat KM. Annu. Rev. Biochem. 80 769-795 (2011)
  27. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo P, Ruvolo V, Evangelisti C, Martelli AM, McCubrey JA. Leukemia 25 1080-1094 (2011)
  28. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Bäsecke J, Stivala F, Donia M, Fagone P, Malaponte G, Mazzarino MC, Nicoletti F, Libra M, Maksimovic-Ivanic D, Mijatovic S, Montalto G, Cervello M, Laidler P, Milella M, Tafuri A, Bonati A, Evangelisti C, Cocco L, Martelli AM, McCubrey JA. Oncotarget 2 135-164 (2011)
  29. Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways. McCubrey JA, Steelman LS, Kempf CR, Chappell WH, Abrams SL, Stivala F, Malaponte G, Nicoletti F, Libra M, Bäsecke J, Maksimovic-Ivanic D, Mijatovic S, Montalto G, Cervello M, Cocco L, Martelli AM. J. Cell. Physiol. 226 2762-2781 (2011)
  30. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Force T, Kolaja KL. Nat Rev Drug Discov 10 111-126 (2011)
  31. Novel mitogen-activated protein kinase kinase inhibitors. Chapman MS, Miner JN. Expert Opin Investig Drugs 20 209-220 (2011)
  32. Targeting Pyk2 for therapeutic intervention. Lipinski CA, Loftus JC. Expert Opin. Ther. Targets 14 95-108 (2010)
  33. Why do kinase inhibitors cause cardiotoxicity and what can be done about it? Cheng H, Force T. Prog Cardiovasc Dis 53 114-120 (2010)
  34. Partner exchange: protein-protein interactions in the Raf pathway. Wimmer R, Baccarini M. Trends Biochem. Sci. 35 660-668 (2010)
  35. Probing the probes: fitness factors for small molecule tools. Workman P, Collins I. Chem. Biol. 17 561-577 (2010)
  36. Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice. Kudo M. Int. J. Clin. Oncol. 15 242-255 (2010)
  37. Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Pratilas CA, Solit DB. Clin. Cancer Res. 16 3329-3334 (2010)
  38. Proteus in the world of proteins: conformational changes in protein kinases. Rabiller M, Getlik M, Klüter S, Richters A, Tückmantel S, Simard JR, Rauh D. Arch. Pharm. (Weinheim) 343 193-206 (2010)
  39. Targeted therapies in cancer. Ciavarella S, Milano A, Dammacco F, Silvestris F. BioDrugs 24 77-88 (2010)
  40. Emerging MEK inhibitors. McCubrey JA, Steelman LS, Abrams SL, Chappell WH, Russo S, Ove R, Milella M, Tafuri A, Lunghi P, Bonati A, Stivala F, Nicoletti F, Libra M, Martelli AM, Montalto G, Cervello M. Expert Opin Emerg Drugs 15 203-223 (2010)
  41. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. Frémin C, Meloche S. J Hematol Oncol 3 8 (2010)
  42. Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases. Haan C, Behrmann I, Haan S. J. Cell. Mol. Med. 14 504-527 (2010)
  43. Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling. Hou DX, Kumamoto T. Antioxid. Redox Signal. 13 691-719 (2010)
  44. Targeting cancer with small molecule kinase inhibitors. Zhang J, Yang PL, Gray NS. Nat. Rev. Cancer 9 28-39 (2009)
  45. A review of kinases implicated in pancreatic cancer. Giroux V, Dagorn JC, Iovanna JL. Pancreatology 9 738-754 (2009)
  46. Targeting mitogen-activated protein kinase kinase (MEK) in solid tumors. Duffy A, Kummar S. Target Oncol 4 267-273 (2009)
  47. Targeting protein kinases in central nervous system disorders. Chico LK, Van Eldik LJ, Watterson DM. Nat Rev Drug Discov 8 892-909 (2009)
  48. Apoptosis and autophagy: BIM as a mediator of tumour cell death in response to oncogene-targeted therapeutics. Gillings AS, Balmanno K, Wiggins CM, Johnson M, Cook SJ. FEBS J. 276 6050-6062 (2009)
  49. Structure-based design of molecular cancer therapeutics. van Montfort RL, Workman P. Trends Biotechnol. 27 315-328 (2009)
  50. The structural basis of allosteric regulation in proteins. Laskowski RA, Gerick F, Thornton JM. FEBS Lett. 583 1692-1698 (2009)
  51. Protein kinase inhibitors: contributions from structure to clinical compounds. Johnson LN. Q. Rev. Biophys. 42 1-40 (2009)
  52. New protein kinase CK2 inhibitors: jumping out of the catalytic box. Prudent R, Cochet C. Chem. Biol. 16 112-120 (2009)
  53. The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl. Eck MJ, Manley PW. Curr. Opin. Cell Biol. 21 288-295 (2009)
  54. Protein promiscuity and its implications for biotechnology. Nobeli I, Favia AD, Thornton JM. Nat. Biotechnol. 27 157-167 (2009)
  55. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. Hum. Mutat. 29 992-1006 (2008)
  56. Linking the kinome and phosphorylome--a comprehensive review of approaches to find kinase targets. Sopko R, Andrews BJ. Mol Biosyst 4 920-933 (2008)
  57. Cardiotoxicity of the new cancer therapeutics--mechanisms of, and approaches to, the problem. Force T, Kerkelä R. Drug Discov. Today 13 778-784 (2008)
  58. The MEK/ERK cascade: from signaling specificity to diverse functions. Shaul YD, Seger R. Biochim. Biophys. Acta 1773 1213-1226 (2007)
  59. Kinase packing defects as drug targets. Crespo A, Fernández A. Drug Discov. Today 12 917-923 (2007)
  60. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Roberts PJ, Der CJ. Oncogene 26 3291-3310 (2007)
  61. Role of mitogen-activated protein kinase kinase 4 in cancer. Whitmarsh AJ, Davis RJ. Oncogene 26 3172-3184 (2007)
  62. Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies. Tortora G, Bianco R, Daniele G, Ciardiello F, McCubrey JA, Ricciardi MR, Ciuffreda L, Cognetti F, Tafuri A, Milella M. Drug Resist. Updat. 10 81-100 (2007)
  63. Toward a molecular classification of melanoma. Fecher LA, Cummings SD, Keefe MJ, Alani RM. J. Clin. Oncol. 25 1606-1620 (2007)
  64. Clinical experience of MEK inhibitors in cancer therapy. Wang D, Boerner SA, Winkler JD, LoRusso PM. Biochim. Biophys. Acta 1773 1248-1255 (2007)
  65. Networks for the allosteric control of protein kinases. Shi Z, Resing KA, Ahn NG. Curr. Opin. Struct. Biol. 16 686-692 (2006)
  66. New approaches to molecular cancer therapeutics. Collins I, Workman P. Nat. Chem. Biol. 2 689-700 (2006)
  67. Potential future therapies for psoriasis. Papp KA. Semin Cutan Med Surg 24 58-63 (2005)
  68. Features of selective kinase inhibitors. Knight ZA, Shokat KM. Chem. Biol. 12 621-637 (2005)

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  1. A quantitative analysis of kinase inhibitor selectivity. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP. Nat. Biotechnol. 26 127-132 (2008)
  2. BRAF mutation predicts sensitivity to MEK inhibition. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N. Nature 439 358-362 (2006)
  3. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE, You MJ, DePinho RA, McMahon M, Bosenberg M. Nat. Genet. 41 544-552 (2009)
  4. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, MacConaill LE, Zhang J, Gray NS, Sellers WR, Dummer R, Garraway LA. Proc. Natl. Acad. Sci. U.S.A. 106 20411-20416 (2009)
  5. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, DeLuca P, Bruzek L, Piens J, Asbury P, Van Becelaere K, Herrera R, Sebolt-Leopold J, Meyer MB. J. Clin. Oncol. 23 5281-5293 (2005)
  6. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, Daniëls V, Lewis P, Jain S, Ding J, Syed A, Thomas KJ, Baekelandt V, Cookson MR. J. Biol. Chem. 283 16906-16914 (2008)
  7. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. Proc. Natl. Acad. Sci. U.S.A. 104 20523-20528 (2007)
  8. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Adrián FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley P, Mestan J, Fabbro D, Gray NS. Nat. Chem. Biol. 2 95-102 (2006)
  9. Genetic predictors of MEK dependence in non-small cell lung cancer. Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, Shigematsu H, Yamamoto H, Sawai A, Janakiraman M, Taylor BS, Pao W, Toyooka S, Ladanyi M, Gazdar A, Rosen N, Solit DB. Cancer Res. 68 9375-9383 (2008)
  10. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. Sci Signal 3 ra84 (2010)
  11. Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Huang Y, Noble NA, Zhang J, Xu C, Border WA. Kidney Int. 72 45-52 (2007)
  12. A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3. Yamamoto M, Standley DM, Takashima S, Saiga H, Okuyama M, Kayama H, Kubo E, Ito H, Takaura M, Matsuda T, Soldati-Favre D, Takeda K. J. Exp. Med. 206 2747-2760 (2009)
  13. A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK. Brennan DF, Dar AC, Hertz NT, Chao WC, Burlingame AL, Shokat KM, Barford D. Nature 472 366-369 (2011)
  14. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Marks JL, Gong Y, Chitale D, Golas B, McLellan MD, Kasai Y, Ding L, Mardis ER, Wilson RK, Solit D, Levine R, Michel K, Thomas RK, Rusch VW, Ladanyi M, Pao W. Cancer Res. 68 5524-5528 (2008)
  15. Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine. Lee KW, Kang NJ, Heo YS, Rogozin EA, Pugliese A, Hwang MK, Bowden GT, Bode AM, Lee HJ, Dong Z. Cancer Res. 68 946-955 (2008)
  16. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Barrett SD, Bridges AJ, Dudley DT, Saltiel AR, Fergus JH, Flamme CM, Delaney AM, Kaufman M, LePage S, Leopold WR, Przybranowski SA, Sebolt-Leopold J, Van Becelaere K, Doherty AM, Kennedy RM, Marston D, Howard WA, Smith Y, Warmus JS, Tecle H. Bioorg. Med. Chem. Lett. 18 6501-6504 (2008)
  17. Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites. Pike AC, Rellos P, Niesen FH, Turnbull A, Oliver AW, Parker SA, Turk BE, Pearl LH, Knapp S. EMBO J. 27 704-714 (2008)
  18. Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. Wu WI, Voegtli WC, Sturgis HL, Dizon FP, Vigers GP, Brandhuber BJ. PLoS ONE 5 e12913 (2010)
  19. Functional proteomics identifies targets of phosphorylation by B-Raf signaling in melanoma. Old WM, Shabb JB, Houel S, Wang H, Couts KL, Yen CY, Litman ES, Croy CH, Meyer-Arendt K, Miranda JG, Brown RA, Witze ES, Schweppe RE, Resing KA, Ahn NG. Mol. Cell 34 115-131 (2009)
  20. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB, Gallardo H, Liu C, Merghoub T, Hefter B, Dolgalev I, Viale A, Heguy A, De Stanchina E, Cobrinik D, Bollag G, Wolchok J, Houghton A, Solit DB. Oncogene 31 446-457 (2012)
  21. A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Catalanotti F, Reyes G, Jesenberger V, Galabova-Kovacs G, de Matos Simoes R, Carugo O, Baccarini M. Nat. Struct. Mol. Biol. 16 294-303 (2009)
  22. Tunable signal processing in synthetic MAP kinase cascades. O'Shaughnessy EC, Palani S, Collins JJ, Sarkar CA. Cell 144 119-131 (2011)
  23. Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Takekawa M, Tatebayashi K, Saito H. Mol. Cell 18 295-306 (2005)
  24. Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Tang N, Marshall WF, McMahon M, Metzger RJ, Martin GR. Science 333 342-345 (2011)
  25. Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain. Lee CC, Jia Y, Li N, Sun X, Ng K, Ambing E, Gao MY, Hua S, Chen C, Kim S, Michellys PY, Lesley SA, Harris JL, Spraggon G. Biochem. J. 430 425-437 (2010)
  26. Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells. Zhu F, Zykova TA, Kang BS, Wang Z, Ebeling MC, Abe Y, Ma WY, Bode AM, Dong Z. Gastroenterology 133 219-231 (2007)
  27. Computational sampling of a cryptic drug binding site in a protein receptor: explicit solvent molecular dynamics and inhibitor docking to p38 MAP kinase. Frembgen-Kesner T, Elcock AH. J. Mol. Biol. 359 202-214 (2006)
  28. MEK1 activation by PAK: a novel mechanism. Park ER, Eblen ST, Catling AD. Cell. Signal. 19 1488-1496 (2007)
  29. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Lito P, Saborowski A, Yue J, Solomon M, Joseph E, Gadal S, Saborowski M, Kastenhuber E, Fellmann C, Ohara K, Morikami K, Miura T, Lukacs C, Ishii N, Lowe S, Rosen N. Cancer Cell 25 697-710 (2014)
  30. Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. Narumi Y, Aoki Y, Niihori T, Neri G, Cavé H, Verloes A, Nava C, Kavamura MI, Okamoto N, Kurosawa K, Hennekam RC, Wilson LC, Gillessen-Kaesbach G, Wieczorek D, Lapunzina P, Ohashi H, Makita Y, Kondo I, Tsuchiya S, Ito E, Sameshima K, Kato K, Kure S, Matsubara Y. Am. J. Med. Genet. A 143A 799-807 (2007)
  31. A novel role for copper in Ras/mitogen-activated protein kinase signaling. Turski ML, Brady DC, Kim HJ, Kim BE, Nose Y, Counter CM, Winge DR, Thiele DJ. Mol. Cell. Biol. 32 1284-1295 (2012)
  32. Discovery of a potential allosteric ligand binding site in CDK2. Betzi S, Alam R, Martin M, Lubbers DJ, Han H, Jakkaraj SR, Georg GI, Schönbrunn E. ACS Chem. Biol. 6 492-501 (2011)
  33. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Ishii N, Harada N, Joseph EW, Ohara K, Miura T, Sakamoto H, Matsuda Y, Tomii Y, Tachibana-Kondo Y, Iikura H, Aoki T, Shimma N, Arisawa M, Sowa Y, Poulikakos PI, Rosen N, Aoki Y, Sakai T. Cancer Res. 73 4050-4060 (2013)
  34. Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design. Han S, Mistry A, Chang JS, Cunningham D, Griffor M, Bonnette PC, Wang H, Chrunyk BA, Aspnes GE, Walker DP, Brosius AD, Buckbinder L. J. Biol. Chem. 284 13193-13201 (2009)
  35. Computational modeling of allosteric communication reveals organizing principles of mutation-induced signaling in ABL and EGFR kinases. Dixit A, Verkhivker GM. PLoS Comput. Biol. 7 e1002179 (2011)
  36. MEK4 function, genistein treatment, and invasion of human prostate cancer cells. Xu L, Ding Y, Catalona WJ, Yang XJ, Anderson WF, Jovanovic B, Wellman K, Killmer J, Huang X, Scheidt KA, Montgomery RB, Bergan RC. J. Natl. Cancer Inst. 101 1141-1155 (2009)
  37. Competing docking interactions can bring about bistability in the MAPK cascade. Legewie S, Schoeberl B, Blüthgen N, Herzel H. Biophys. J. 93 2279-2288 (2007)
  38. Oncogenic Ras abrogates MEK SUMOylation that suppresses the ERK pathway and cell transformation. Kubota Y, O'Grady P, Saito H, Takekawa M. Nat. Cell Biol. 13 282-291 (2011)
  39. Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex. Jacobs MD, Caron PR, Hare BJ. Proteins 70 1451-1460 (2008)
  40. Crystal structure of domain-swapped STE20 OSR1 kinase domain. Lee SJ, Cobb MH, Goldsmith EJ. Protein Sci. 18 304-313 (2009)
  41. MEK1 binds directly to betaarrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline-stimulated internalization. Meng D, Lynch MJ, Huston E, Beyermann M, Eichhorst J, Adams DR, Klussmann E, Houslay MD, Baillie GS. J. Biol. Chem. 284 11425-11435 (2009)
  42. Allosteric interactions between the myristate- and ATP-site of the Abl kinase. Iacob RE, Zhang J, Gray NS, Engen JR. PLoS ONE 6 e15929 (2011)
  43. 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography is a sensitive method for imaging the response of BRAF-dependent tumors to MEK inhibition. Solit DB, Santos E, Pratilas CA, Lobo J, Moroz M, Cai S, Blasberg R, Sebolt-Leopold J, Larson S, Rosen N. Cancer Res. 67 11463-11469 (2007)
  44. Resistance of Akt kinases to dephosphorylation through ATP-dependent conformational plasticity. Chan TO, Zhang J, Rodeck U, Pascal JM, Armen RS, Spring M, Dumitru CD, Myers V, Li X, Cheung JY, Feldman AM. Proc. Natl. Acad. Sci. U.S.A. 108 E1120-7 (2011)
  45. Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. Anastasaki C, Estep AL, Marais R, Rauen KA, Patton EE. Hum. Mol. Genet. 18 2543-2554 (2009)
  46. Fluorine-protein interactions and ¹⁹F NMR isotropic chemical shifts: An empirical correlation with implications for drug design. Dalvit C, Vulpetti A. ChemMedChem 6 104-114 (2011)
  47. The Salmonella kinase SteC targets the MAP kinase MEK to regulate the host actin cytoskeleton. Odendall C, Rolhion N, Förster A, Poh J, Lamont DJ, Liu M, Freemont PS, Catling AD, Holden DW. Cell Host Microbe 12 657-668 (2012)
  48. The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation. Gao M, Skolnick J. Proc. Natl. Acad. Sci. U.S.A. 109 3784-3789 (2012)
  49. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes. Sicard A, Semblat JP, Doerig C, Hamelin R, Moniatte M, Dorin-Semblat D, Spicer JA, Srivastava A, Retzlaff S, Heussler V, Waters AP, Doerig C. Cell. Microbiol. 13 836-845 (2011)
  50. MEK1/2 inhibition elicits regression of autochthonous lung tumors induced by KRASG12D or BRAFV600E. Trejo CL, Juan J, Vicent S, Sweet-Cordero A, McMahon M. Cancer Res. 72 3048-3059 (2012)
  51. Mitogen-activated protein kinase (MAPK)-docking sites in MAPK kinases function as tethers that are crucial for MAPK regulation in vivo. Grewal S, Molina DM, Bardwell L. Cell. Signal. 18 123-134 (2006)
  52. MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism. Pei XY, Dai Y, Tenorio S, Lu J, Harada H, Dent P, Grant S. Blood 110 2092-2101 (2007)
  53. Involvement of c-Met/hepatocyte growth factor pathway in cholangiocarcinoma cell invasion and its therapeutic inhibition with small interfering RNA specific for c-Met. Leelawat K, Leelawat S, Tepaksorn P, Rattanasinganchan P, Leungchaweng A, Tohtong R, Sobhon P. J. Surg. Res. 136 78-84 (2006)
  54. Identification of coumarin derivatives as a novel class of allosteric MEK1 inhibitors. Han S, Zhou V, Pan S, Liu Y, Hornsby M, McMullan D, Klock HE, Haugen J, Lesley SA, Gray N, Caldwell J, Gu XJ. Bioorg. Med. Chem. Lett. 15 5467-5473 (2005)
  55. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Boasberg PD, Redfern CH, Daniels GA, Bodkin D, Garrett CR, Ricart AD. Cancer Chemother. Pharmacol. 68 547-552 (2011)
  56. A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway. Seyfried J, Wang X, Kharebava G, Tournier C. Mol. Cell. Biol. 25 9820-9828 (2005)
  57. Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). Rice KD, Aay N, Anand NK, Blazey CM, Bowles OJ, Bussenius J, Costanzo S, Curtis JK, Defina SC, Dubenko L, Engst S, Joshi AA, Kennedy AR, Kim AI, Koltun ES, Lougheed JC, Manalo JC, Martini JF, Nuss JM, Peto CJ, Tsang TH, Yu P, Johnston S. ACS Med Chem Lett 3 416-421 (2012)
  58. MEK inhibitors as a chemotherapeutic intervention in multiple myeloma. Chang-Yew Leow C, Gerondakis S, Spencer A. Blood Cancer J 3 e105 (2013)
  59. "RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway. Cseh B, Doma E, Baccarini M. FEBS Lett. 588 2398-2406 (2014)
  60. A novel approach to the discovery of small-molecule ligands of CDK2. Martin MP, Alam R, Betzi S, Ingles DJ, Zhu JY, Schönbrunn E. Chembiochem 13 2128-2136 (2012)
  61. Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Cowan-Jacob SW, Jahnke W, Knapp S. Future Med Chem 6 541-561 (2014)
  62. Coffee phenolic phytochemicals suppress colon cancer metastasis by targeting MEK and TOPK. Kang NJ, Lee KW, Kim BH, Bode AM, Lee HJ, Heo YS, Boardman L, Limburg P, Lee HJ, Dong Z. Carcinogenesis 32 921-928 (2011)
  63. Structural requirements for Yersinia YopJ inhibition of MAP kinase pathways. Hao YH, Wang Y, Burdette D, Mukherjee S, Keitany G, Goldsmith E, Orth K. PLoS ONE 3 e1375 (2008)
  64. Estrogen receptor-positive breast cancer molecular signatures and therapeutic potentials (Review). Zhang MH, Man HT, Zhao XD, Dong N, Ma SL. Biomed Rep 2 41-52 (2014)
  65. Diminished WNT -> β-catenin -> c-MYC signaling is a barrier for malignant progression of BRAFV600E-induced lung tumors. Juan J, Muraguchi T, Iezza G, Sears RC, McMahon M. Genes Dev. 28 561-575 (2014)
  66. Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles. Georghiou G, Kleiner RE, Pulkoski-Gross M, Liu DR, Seeliger MA. Nat. Chem. Biol. 8 366-374 (2012)
  67. Evolution of CASK into a Mg2+-sensitive kinase. Mukherjee K, Sharma M, Jahn R, Wahl MC, Südhof TC. Sci Signal 3 ra33 (2010)
  68. Specific phosphorylation and activation of ERK1c by MEK1b: a unique route in the ERK cascade. Shaul YD, Gibor G, Plotnikov A, Seger R. Genes Dev. 23 1779-1790 (2009)
  69. MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM. Rambal AA, Panaguiton ZL, Kramer L, Grant S, Harada H. Leukemia 23 1744-1754 (2009)
  70. Cyanidin suppresses ultraviolet B-induced COX-2 expression in epidermal cells by targeting MKK4, MEK1, and Raf-1. Kim JE, Kwon JY, Seo SK, Son JE, Jung SK, Min SY, Hwang MK, Heo YS, Lee KW, Lee HJ. Biochem. Pharmacol. 79 1473-1482 (2010)
  71. Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling. Haling JR, Sudhamsu J, Yen I, Sideris S, Sandoval W, Phung W, Bravo BJ, Giannetti AM, Peck A, Masselot A, Morales T, Smith D, Brandhuber BJ, Hymowitz SG, Malek S. Cancer Cell 26 402-413 (2014)
  72. Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. Uitdehaag JC, de Roos JA, van Doornmalen AM, Prinsen MB, de Man J, Tanizawa Y, Kawase Y, Yoshino K, Buijsman RC, Zaman GJ. PLoS ONE 9 e92146 (2014)
  73. QIKS--Quantitative identification of kinase substrates. Morandell S, Grosstessner-Hain K, Roitinger E, Hudecz O, Lindhorst T, Teis D, Wrulich OA, Mazanek M, Taus T, Ueberall F, Mechtler K, Huber LA. Proteomics 10 2015-2025 (2010)
  74. Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6. Heise CE, Murray J, Augustyn KE, Bravo B, Chugha P, Cohen F, Giannetti AM, Gibbons P, Hannoush RN, Hearn BR, Jaishankar P, Ly CQ, Shah K, Stanger K, Steffek M, Tang Y, Zhao X, Lewcock JW, Renslo AR, Flygare J, Arkin MR. PLoS ONE 7 e50864 (2012)
  75. Comment Cancer drugs to treat birth defects. Wilkie AO. Nat. Genet. 39 1057-1059 (2007)
  76. Identification and characterization of a novel chemotype MEK inhibitor able to alter the phosphorylation state of MEK1/2. Yoshida T, Kakegawa J, Yamaguchi T, Hantani Y, Okajima N, Sakai T, Watanabe Y, Nakamura M. Oncotarget 3 1533-1545 (2012)
  77. Delphinidin attenuates neoplastic transformation in JB6 Cl41 mouse epidermal cells by blocking Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling. Kang NJ, Lee KW, Kwon JY, Hwang MK, Rogozin EA, Heo YS, Bode AM, Lee HJ, Dong Z. Cancer Prev Res (Phila) 1 522-531 (2008)
  78. Structure of the OSR1 kinase, a hypertension drug target. Villa F, Deak M, Alessi DR, van Aalten DM. Proteins 73 1082-1087 (2008)
  79. Non-ATP competitive protein kinase inhibitors as anti-tumor therapeutics. Kirkland LO, McInnes C. Biochem. Pharmacol. 77 1561-1571 (2009)
  80. Mutationally activated PIK3CA(H1047R) cooperates with BRAF(V600E) to promote lung cancer progression. Trejo CL, Green S, Marsh V, Collisson EA, Iezza G, Phillips WA, McMahon M. Cancer Res. 73 6448-6461 (2013)
  81. Strategies for the NMR-based identification and optimization of allosteric protein kinase inhibitors. Jahnke W, Blommers MJ, Fernández C, Zwingelstein C, Amstutz R. Chembiochem 6 1607-1610 (2005)
  82. Small-molecule inhibitors binding to protein kinase. Part II: the novel pharmacophore approach of type II and type III inhibition. Backes A, Zech B, Felber B, Klebl B, Müller G. Expert Opin Drug Discov 3 1427-1449 (2008)
  83. The structure of the MAP2K MEK6 reveals an autoinhibitory dimer. Min X, Akella R, He H, Humphreys JM, Tsutakawa SE, Lee SJ, Tainer JA, Cobb MH, Goldsmith EJ. Structure 17 96-104 (2009)
  84. Computer-aided drug design: the next 20 years. Van Drie JH. J. Comput. Aided Mol. Des. 21 591-601 (2007)
  85. Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy. McCubrey JA, Sokolosky ML, Lehmann BD, Taylor JR, Navolanic PM, Chappell WH, Abrams SL, Stadelman KM, Wong EW, Misaghian N, Horn S, Bäsecke J, Libra M, Stivala F, Ligresti G, Tafuri A, Milella M, Zarzycki M, Dzugaj A, Chiarini F, Evangelisti C, Martelli AM, Terrian DM, Franklin RA, Steelman LS. Adv. Enzyme Regul. 48 113-135 (2008)
  86. Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK? Tecle H, Shao J, Li Y, Kothe M, Kazmirski S, Penzotti J, Ding YH, Ohren J, Moshinsky D, Coli R, Jhawar N, Bora E, Jacques-O'Hagan S, Wu J. Bioorg. Med. Chem. Lett. 19 226-229 (2009)
  87. Dimerization in protein kinase signaling. Pelech S. J. Biol. 5 12 (2006)
  88. A noncompetitive inhibitor for Mycobacterium tuberculosis's class IIa fructose 1,6-bisphosphate aldolase. Capodagli GC, Sedhom WG, Jackson M, Ahrendt KA, Pegan SD. Biochemistry 53 202-213 (2014)
  89. Inhibition of MAP2K and GSK3 signaling promotes bovine blastocyst development and epiblast-associated expression of pluripotency factors. Harris D, Huang B, Oback B. Biol. Reprod. 88 74 (2013)
  90. Analysis of conditions affecting auto-phosphorylation of human kinases during expression in bacteria. Shrestha A, Hamilton G, O'Neill E, Knapp S, Elkins JM. Protein Expr. Purif. 81 136-143 (2012)
  91. Identification of isothiazole-4-carboxamidines derivatives as a novel class of allosteric MEK1 inhibitors. El Abdellaoui H, Varaprasad CV, Barawkar D, Chakravarty S, Maderna A, Tam R, Chen H, Allan M, Wu JZ, Appleby T, Yan S, Zhang W, Lang S, Yao N, Hamatake R, Hong Z. Bioorg. Med. Chem. Lett. 16 5561-5566 (2006)
  92. Inhibition of vascular smooth muscle cell proliferation by Gentiana lutea root extracts. Kesavan R, Potunuru UR, Nastasijević B, T A, Joksić G, Dixit M. PLoS ONE 8 e61393 (2013)
  93. Targeting the unactivated conformations of protein kinases for small molecule drug discovery. Alton GR, Lunney EA. Expert Opin Drug Discov 3 595-605 (2008)
  94. Targeting oncogenic BRAF in human cancer. Pratilas CA, Xing F, Solit DB. Curr. Top. Microbiol. Immunol. 355 83-98 (2012)
  95. trans-Resveratrol inhibits H2O2-induced adenocarcinoma gastric cells proliferation via inactivation of MEK1/2-ERK1/2-c-Jun signalling axis. Aquilano K, Baldelli S, Rotilio G, Ciriolo MR. Biochem. Pharmacol. 77 337-347 (2009)
  96. 2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase). Warmus JS, Flamme C, Zhang LY, Barrett S, Bridges A, Chen H, Gowan R, Kaufman M, Sebolt-Leopold J, Leopold W, Merriman R, Ohren J, Pavlovsky A, Przybranowski S, Tecle H, Valik H, Whitehead C, Zhang E. Bioorg. Med. Chem. Lett. 18 6171-6174 (2008)
  97. The resveratrol analogue 3,5,3',4',5'-pentahydroxy-trans-stilbene inhibits cell transformation via MEK. Lee KW, Kang NJ, Rogozin EA, Oh SM, Heo YS, Pugliese A, Bode AM, Lee HJ, Dong Z. Int. J. Cancer 123 2487-2496 (2008)
  98. Constitutive MEK1 activation rescues anthrax lethal toxin-induced vascular effects in vivo. Bolcome RE, Chan J. Infect. Immun. 78 5043-5053 (2010)
  99. Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways. García-Echeverría C. Purinergic Signal. 5 117-125 (2009)
  100. Detection of secondary binding sites in proteins using fragment screening. Ludlow RF, Verdonk ML, Saini HK, Tickle IJ, Jhoti H. Proc. Natl. Acad. Sci. U.S.A. 112 15910-15915 (2015)
  101. Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor. Van Dort ME, Galbán S, Wang H, Sebolt-Leopold J, Whitehead C, Hong H, Rehemtulla A, Ross BD. Bioorg. Med. Chem. 23 1386-1394 (2015)
  102. A chrysin derivative suppresses skin cancer growth by inhibiting cyclin-dependent kinases. Liu H, Liu K, Huang Z, Park CM, Thimmegowda NR, Jang JH, Ryoo IJ, He L, Kim SO, Oi N, Lee KW, Soung NK, Bode AM, Yang Y, Zhou X, Erikson RL, Ahn JS, Hwang J, Kim KE, Dong Z, Kim BY. J. Biol. Chem. 288 25924-25937 (2013)
  103. Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. Little AS, Balmanno K, Sale MJ, Smith PD, Cook SJ. Biochem. Soc. Trans. 40 73-78 (2012)
  104. Fully activated MEK1 exhibits compromised affinity for binding of allosteric inhibitors U0126 and PD0325901. Sheth PR, Liu Y, Hesson T, Zhao J, Vilenchik L, Liu YH, Mayhood TW, Le HV. Biochemistry 50 7964-7976 (2011)
  105. Inactivation of rho GTPases by statins attenuates anthrax lethal toxin activity. deCathelineau AM, Bokoch GM. Infect. Immun. 77 348-359 (2009)
  106. Delineation of Polypharmacology across the Human Structural Kinome Using a Functional Site Interaction Fingerprint Approach. Zhao Z, Xie L, Xie L, Bourne PE. J. Med. Chem. 59 4326-4341 (2016)
  107. Expression and purification of phosphorylated and non-phosphorylated human MEK1. Smith CK, Carr D, Mayhood TW, Jin W, Gray K, Windsor WT. Protein Expr. Purif. 52 446-456 (2007)
  108. Optical control of cell signaling by single-chain photoswitchable kinases. Zhou XX, Fan LZ, Li P, Shen K, Lin MZ. Science 355 836-842 (2017)
  109. Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells. Cossa G, Lanzi C, Cassinelli G, Carenini N, Arrighetti N, Gatti L, Corna E, Zunino F, Zaffaroni N, Perego P. Cancer Lett. 347 212-224 (2014)
  110. Detection of allosteric kinase inhibitors by displacement of active site probes. Lebakken CS, Reichling LJ, Ellefson JM, Riddle SM. J Biomol Screen 17 813-821 (2012)
  111. Engineering human MEK-1 for structural studies: A case study of combinatorial domain hunting. Meier C, Brookings DC, Ceska TA, Doyle C, Gong H, McMillan D, Saville GP, Mushtaq A, Knight D, Reich S, Pearl LH, Powell KA, Savva R, Allen RA. J. Struct. Biol. 177 329-334 (2012)
  112. Mitogen-activated protein/extracellular signal-regulated kinase kinase 1act/tubulin interaction is an important determinant of mitotic stability in cultured HT1080 human fibrosarcoma cells. Cao JN, Shafee N, Vickery L, Kaluz S, Ru N, Stanbridge EJ. Cancer Res. 70 6004-6014 (2010)
  113. Improved yields for baculovirus-mediated expression of human His(6)-PDK1 and His(6)-PKBbeta/Akt2 and characterization of phospho-specific isoforms for design of inhibitors that stabilize inactive conformations. Gao X, Yo P, Harris TK. Protein Expr. Purif. 43 44-56 (2005)
  114. Letter The use of virtual screening and differential scanning fluorimetry for the rapid identification of fragments active against MEK1. Amaning K, Lowinski M, Vallee F, Steier V, Marcireau C, Ugolini A, Delorme C, Foucalt F, McCort G, Derimay N, Andouche C, Vougier S, Llopart S, Halland N, Rak A. Bioorg. Med. Chem. Lett. 23 3620-3626 (2013)
  115. Discovery and characterization of novel allosteric FAK inhibitors. Iwatani M, Iwata H, Okabe A, Skene RJ, Tomita N, Hayashi Y, Aramaki Y, Hosfield DJ, Hori A, Baba A, Miki H. Eur J Med Chem 61 49-60 (2013)
  116. Fused thiophene derivatives as MEK inhibitors. Laing VE, Brookings DC, Carbery RJ, Simorte JG, Hutchings MC, Langham BJ, Lowe MA, Allen RA, Fetterman JR, Turner J, Meier C, Kennedy J, Merriman M. Bioorg. Med. Chem. Lett. 22 472-475 (2012)
  117. Regulation of Plasmodium falciparum Pfnek3 relies on phosphorylation at its activation loop and at threonine 82. Low H, Chua CS, Sim TS. Cell. Mol. Life Sci. 66 3081-3090 (2009)
  118. Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors. Vijayan RS, He P, Modi V, Duong-Ly KC, Ma H, Peterson JR, Dunbrack RL, Levy RM. J. Med. Chem. 58 466-479 (2015)
  119. Resistance to Selumetinib (AZD6244) in colorectal cancer cell lines is mediated by p70S6K and RPS6 activation. Grasso S, Tristante E, Saceda M, Carbonell P, Mayor-López L, Carballo-Santana M, Carrasco-García E, Rocamora-Reverte L, García-Morales P, Carballo F, Ferragut JA, Martínez-Lacaci I. Neoplasia 16 845-860 (2014)
  120. Selectively targeting an inactive conformation of interleukin-2-inducible T-cell kinase by allosteric inhibitors. Han S, Czerwinski RM, Caspers NL, Limburg DC, Ding W, Wang H, Ohren JF, Rajamohan F, McLellan TJ, Unwalla R, Choi C, Parikh MD, Seth N, Edmonds J, Phillips C, Shakya S, Li X, Spaulding V, Hughes S, Cook A, Robinson C, Mathias JP, Navratilova I, Medley QG, Anderson DR, Kurumbail RG, Aulabaugh A. Biochem. J. 460 211-222 (2014)
  121. Synthesis, quantitative structure-activity relationship and biological evaluation of 1,3,4-oxadiazole derivatives possessing diphenylamine moiety as potential anticancer agents. Abdel Rahman DE. Chem. Pharm. Bull. 61 151-159 (2013)
  122. Development of a time-resolved fluorescence resonance energy transfer assay for cyclin-dependent kinase 4 and identification of its ATP-noncompetitive inhibitors. Lo MC, Ngo R, Dai K, Li C, Liang L, Lee J, Emkey R, Eksterowicz J, Ventura M, Young SW, Xiao SH. Anal. Biochem. 421 368-377 (2012)
  123. A full-length 3D structure for MAPK/ERK kinase 2 (MEK2). Liang H, Liu T, Chen F, Liu Z, Liu S. Sci China Life Sci 54 336-341 (2011)
  124. Reconstitution of modular PDK1 functions on trans-splicing of the regulatory PH and catalytic kinase domains. Al-Ali H, Ragan TJ, Gao X, Harris TK. Bioconjug. Chem. 18 1294-1302 (2007)
  125. Targeting ERK1/2-bim signaling cascades by BH3-mimetic ABT-737 as an alternative therapeutic strategy for oral cancer. Shin JA, Kim LH, Lee SJ, Jeong JH, Jung JY, Lee HN, Hong IS, Cho SD. Oncotarget 6 35667-35683 (2015)
  126. Selumetinib for the treatment of cancer. Ciombor KK, Bekaii-Saab T. Expert Opin Investig Drugs 24 111-123 (2015)
  127. Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity. Gysin S, Paquette J, McMahon M. Mol. Cancer Res. 10 1607-1619 (2012)
  128. Cell-based apoptosis assays in oncology drug discovery. Drewe J, Cai SX. Expert Opin Drug Discov 5 583-596 (2010)
  129. The MEK2-binding tumor suppressor hDlg is recruited by E-cadherin to the midbody ring. Gaudet S, Langlois MJ, Lue RA, Rivard N, Viel A. BMC Cell Biol. 12 55 (2011)
  130. 3D-QSAR and molecular docking studies on substituted isothiazole analogs as inhibitors against MEK-1 kinase. Reddy BM, Tanneeru K, Meetei PA, Guruprasad L. Chem Biol Drug Des 79 84-91 (2012)
  131. Yeast two-hybrid junk sequences contain selected linear motifs. Liu Y, Woods NT, Kim D, Sweet M, Monteiro AN, Karchin R. Nucleic Acids Res. 39 e128 (2011)
  132. CInQ-03, a novel allosteric MEK inhibitor, suppresses cancer growth in vitro and in vivo. Kim DJ, Lee MH, Reddy K, Li Y, Lim DY, Xie H, Lee SY, Yeom YI, Bode AM, Dong Z. Carcinogenesis 34 1134-1143 (2013)
  133. Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression. Woodfield SE, Zhang L, Scorsone KA, Liu Y, Zage PE. BMC Cancer 16 172 (2016)
  134. Examining Ligand-Based Stabilization of Proteins in Cells with MEK1 Kinase Inhibitors. Auld DS, Davis CA, Jimenez M, Knight S, Orme JP. Assay Drug Dev Technol 13 266-276 (2015)
  135. 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 KD, Lee W, Eigenbrot C, Ultsch M, Wiesmann C, Heald R, Price S, Hewitt J, Jackson P, Savy P, Burton B, Choo EF, Pang J, Boggs J, Yang A, Yang X, Baumgardner M. Bioorg. Med. Chem. Lett. 24 4714-4723 (2014)
  136. 5-Carboxyfluorescein tagged N-phenylanthranilamide as a tracer reagent for fluorescence polarization: a robust method to screen MAPK pathway allosteric inhibitors. Rezvani ZN, Mayer RJ, Chan WC. Chem. Commun. (Camb.) 46 2043-2045 (2010)
  137. Allosteric Communication Networks in Proteins Revealed through Pocket Crosstalk Analysis. La Sala G, Decherchi S, De Vivo M, Rocchia W. ACS Cent Sci 3 949-960 (2017)
  138. Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome. Zhao Z, Xie L, Bourne PE. PLoS ONE 12 e0179936 (2017)
  139. Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1. Weijman JF, Kumar A, Jamieson SA, King CM, Caradoc-Davies TT, Ledgerwood EC, Murphy JM, Mace PD. Proc. Natl. Acad. Sci. U.S.A. 114 E2096-E2105 (2017)
  140. Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes. Lee LH, Gasilina A, Roychoudhury J, Clark J, McCormack FX, Pressey J, Grimley MS, Lorsbach R, Ali S, Bailey M, Stephens P, Ross JS, Miller VA, Nassar NN, Kumar AR. JCI Insight 2 e89473 (2017)
  141. Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics. Loviglio MN, Beck CR, White JJ, Leleu M, Harel T, Guex N, Niknejad A, Bi W, Chen ES, Crespo I, Yan J, Charng WL, Gu S, Fang P, Coban-Akdemir Z, Shaw CA, Jhangiani SN, Muzny DM, Gibbs RA, Rougemont J, Xenarios I, Lupski JR, Reymond A. Genome Med 8 105 (2016)
  142. A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors. Kasuga A, Nakagawa K, Nagashima F, Shimizu T, Naruge D, Nishina S, Kitamura H, Kurata T, Takasu A, Fujisaka Y, Okamoto W, Nishimura Y, Mukaiyama A, Matsushita H, Furuse J. Invest New Drugs 33 1058-1067 (2015)
  143. Structural and biochemical insights into the activation mechanisms of germinal center kinase OSR1. Li C, Feng M, Shi Z, Hao Q, Song X, Wang W, Zhao Y, Jiao S, Zhou Z. J. Biol. Chem. 289 35969-35978 (2014)
  144. Structure-based design and synthesis of bicyclic fused-pyridines as MEK inhibitors. Lu H, Tu W, Fei H, Xu G, Hu Q, Zhang L, Lin B, Yuan J, Yin J, Gong A, Wan M, Wang D, Zhu X, Feng J, Wang Q, Sun P. Bioorg. Med. Chem. Lett. 24 2555-2559 (2014)
  145. Alternative assay formats to identify diverse inhibitors of protein kinases. Singh P, Ward WH. Expert Opin Drug Discov 3 819-831 (2008)
  146. A protein relational database and protein family knowledge bases to facilitate structure-based design analyses. Mobilio D, Walker G, Brooijmans N, Nilakantan R, Denny RA, Dejoannis J, Feyfant E, Kowticwar RK, Mankala J, Palli S, Punyamantula S, Tatipally M, John RK, Humblet C. Chem Biol Drug Des 76 142-153 (2010)
  147. Novel zebrafish model reveals a critical role for MAPK in lymphangiogenesis. Fevurly RD, Hasso S, Fye A, Fishman SJ, Chan J. J. Pediatr. Surg. 47 177-182 (2012)
  148. New small-molecule inhibitors of mitogen-activated protein kinase kinase. Spicer JA. Expert Opin Drug Discov 3 801-817 (2008)
  149. Towards the development of chromone-based MEK1/2 modulators. Redwan IN, Dyrager C, Solano C, Fernández de Trocóniz G, Voisin L, Bliman D, Meloche S, Grøtli M. Eur J Med Chem 85 127-138 (2014)
  150. Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K). Van Dort ME, Hong H, Wang H, Nino CA, Lombardi RL, Blanks AE, Galbán S, Ross BD. J. Med. Chem. 59 2512-2522 (2016)
  151. PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK. Lu T, Zou Y, Xu G, Potter JA, Taylor GL, Duan Q, Yang Q, Xiong H, Qiu H, Ye D, Zhang P, Yu S, Yuan X, Zhu F, Wang Y, Xiong H. Oncotarget 7 83017-83030 (2016)
  152. Silymarin and its active component silibinin act as novel therapeutic alternatives for salivary gland cancer by targeting the ERK1/2-Bim signaling cascade. Choi ES, Oh S, Jang B, Yu HJ, Shin JA, Cho NP, Yang IH, Won DH, Kwon HJ, Hong SD, Cho SD. Cell Oncol (Dordr) 40 235-246 (2017)
  153. Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi. Yeh I, Lang UE, Durieux E, Tee MK, Jorapur A, Shain AH, Haddad V, Pissaloux D, Chen X, Cerroni L, Judson RL, LeBoit PE, McCalmont TH, Bastian BC, de la Fouchardière A. Nat Commun 8 644 (2017)