25 Years of small molecular weight kinase inhibitors: Potentials and limitations

Molecular Pharmacology

Volumn 87, Issue 5, 2015, Pages 766-775

  Fabbro, Doriano ^a  

^a Piqur Therapeutics AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

LIPID; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN; PROTEIN KINASE; MOLECULAR LIBRARY; PROTEIN KINASE INHIBITOR;

CARDIOVASCULAR DISEASE; DEREGULATION; DIABETES MELLITUS; DRUG APPROVAL; DRUG DEVELOPMENT; DRUG INDUSTRY; DRUG RESISTANCE; HUMAN; INFECTION; INFLAMMATORY DISEASE; MOLECULAR WEIGHT; NONHUMAN; PRIORITY JOURNAL; SHORT SURVEY; ANIMAL; METABOLISM; MOLECULAR LIBRARY; NEOPLASMS; PHARMACOLOGY; PROCEDURES; THERAPEUTIC USE;

ANIMALS; DRUG DISCOVERY; HUMANS; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; SMALL MOLECULE LIBRARIES;

EID: 84929941558     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.114.095489     Document Type: Short Survey

References (162)

1. Adrián FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, and Manley P et al. (2006) Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat Chem Biol 2:95-102.
2. Akinleye A, Furqan M, and Adekunle O (2014) Ibrutinib and indolent B-cell lymphomas. Clin Lymphoma Myeloma Leuk 14:253-260.
3. Ali S and Ali S (2007) Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). Gene 401:38-45.
4. Andraos R, Qian Z, Bonenfant D, Rubert J, Vangrevelinghe E, Scheufler C, Marque F, Régnier CH, De Pover A, and Ryckelynck H et al. (2012) Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov 2:512-523.
5. Apperley JF (2007) Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 8:1018-1029.
6. Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, and Kinzler KW et al. (2003) Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300:949.
7. Barnett SF, Defeo-Jones D, Fu S, Hancock PJ, Haskell KM, Jones RE, Kahana JA, Kral AM, Leander K, and Lee LL et al. (2005) Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem J 385:399-408.
8. Bishop AC (2004) A hot spot for protein kinase inhibitor sensitivity. Chem Biol 11:587-589.
9. Blencke S, Zech B, Engkvist O, Greff Z, Orfi L, Horváth Z, Kéri G, Ullrich A, and Daub H (2004) Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors. Chem Biol 11:691-701.
10. Blume-Jensen P and Hunter T (2001) Oncogenic kinase signalling. Nature 411:355-365.
11. Bono F, De Smet F, Herbert C, De Bock K, Georgiadou M, Fons P, Tjwa M, Alcouffe C, Ny A, and Bianciotto M et al. (2013) Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell 23:477-488.
12. Boudeau J, Miranda-Saavedra D, Barton GJ, and Alessi DR (2006) Emerging roles of pseudokinases. Trends Cell Biol 16:443-452.
13. Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Müller U, Murakami M, Radimerski T, and Bentires-Alj M (2012) JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 22:796-811.
14. Busschots K, Lopez-Garcia LA, Lammi C, Stroba A, Zeuzem S, Piiper A, Alzari PM, Neimanis S, Arencibia JM, and Engel M et al. (2012) Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site. Chem Biol 19:1152-1163.
15. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, and Wierda WG et al. (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369:32-42.
16. Cazorla M, Jouvenceau A, Rose C, Guilloux JP, Pilon C, Dranovsky A, and Prémont J (2010) Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice. PLoS ONE 5:e9777.
17. Chandarlapaty S (2012) Negative feedback and adaptive resistance to the targeted therapy of cancer. Cancer Discov 2:311-319.
18. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, and Maio M et al.; BRIM-3 Study Group (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507-2516.
19. Cheng H and Force T (2010) Why do kinase inhibitors cause cardiotoxicity and what can be done about it? Prog Cardiovasc Dis 53:114-120.
20. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Jr, and Leahy DJ (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421:756-760.
21. Christopoulos A, Changeux JP, Catterall WA, Fabbro D, Burris TP, Cidlowski JA, Olsen RW, Peters JA, Neubig RR, and Pin JP et al. (2014) International union of basic and clinical pharmacology. XC. Multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev 66:918-947.
22. Cohen P (2002) Protein kinases - the major drug targets of the twenty-first century? Nat Rev Drug Discov 1:309-315.
23. Comess KM, Sun C, Abad-Zapatero C, Goedken ER, Gum RJ, Borhani DW, Argiriadi M, Groebe DR, Jia Y, and Clampit JE et al. (2011) Discovery and characterization of non-ATP site inhibitors of the mitogen activated protein (MAP) kinases. ACS Chem Biol 6:234-244.
24. Converso A, Hartingh T, Garbaccio RM, Tasber E, Rickert K, Fraley ME, Yan Y, Kreatsoulas C, Stirdivant S, and Drakas B et al. (2009) Development of thioquinazolinones, allosteric Chk1 kinase inhibitors. Bioorg Med Chem Lett 19:1240-1244.
25. Cools J, Mentens N, Furet P, Fabbro D, Clark JJ, Griffin JD, Marynen P, and Gilliland DG (2004) Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res 64:6385-6389.
26. Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM, Curley DP, Duclos N, Rowan R, and Kutok JL et al. (2003) PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease. Cancer Cell 3:459-469.
27. Courtney KD, Corcoran RB, and Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28:1075-1083.
28. Cowan-Jacob SW (2006) Structural biology of protein tyrosine kinases. Cell Mol Life Sci 63:2608-2625.
29. Cowan-Jacob SW, Jahnke W, and Knapp S (2014) Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Future Med Chem 6:541-561.
30. Cowan-Jacob SW, Möbitz H, and Fabbro D (2009) Structural biology contributions to tyrosine kinase drug discovery. Curr Opin Cell Biol 21:280-287.
31. Dalzell MD (2013) Ponatinib pulled off market over safety issues. Manag Care 22:42-43.
32. Daub H, Specht K, and Ullrich A (2004) Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov 3:1001-1010.
33. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550-562.
34. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, and Song Y et al. (2008b) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351-1356.
35. Engelman JA and Settleman J (2008a) Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev 18:73-79.
36. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, and Christensen J et al. (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039-1043.
37. Fabbro D, Cowan-Jacob SW, Möbitz H, and Martiny-Baron G (2011) Targeting cancer with small-molecular-weight kinase inhibitors. Methods Mol Biol 795:1-34.
38. Fabbro D, Fendrich G, Guez V, Meyer T, Furet P, Mestan P, Griffin JD, Manley PW, and Cowan-Jacob SW (2005). Targeted therapy with imatinib: an exception or a rule?, in Inhibitors of Protein Kinases and Protein Phosphates (Pinna LA and Cohen PTW eds) vol 167, 361-389, Springer, New York.
39. Fabbro D and García-Echeverría C (2002a) Targeting protein kinases in cancer therapy. Curr Opin Drug Discov Devel 5:701-712.
40. Fabbro D, Manley PW, Jahnke W, Liebetanz J, Szyttenholm A, Fendrich G, Strauss A, Zhang J, Gray NS, and Adrian F et al. (2010) Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site. Biochim Biophys Acta 1804:454-462.
41. Fabbro D, Ruetz S, Buchdunger E, Cowan-Jacob SW, Fendrich G, Liebetanz J, Mestan J, O'Reilly T, Traxler P, and Chaudhuri B et al. (2002b) Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther 93:79-98.
42. Faivre S, Demetri G, Sargent W, and Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734-745.
43. Fedorov O, Müller S, and Knapp S (2010) The (un)targeted cancer kinome. Nat Chem Biol 6:166-169.
44. Felip E, Santarpia M, and Rosell R (2007) Emerging drugs for non-small-cell lung cancer. Expert Opin Emerg Drugs 12:449-460.
45. Fleishman SJ, Schlessinger J, and Ben-Tal N (2002) A putative molecular-activation switch in the transmembrane domain of erbB2. Proc Natl Acad Sci USA 99:15937-15940.
46. Fletcher JA and Rubin BP (2007) KIT mutations in GIST. Curr Opin Genet Dev 17:3-7.
47. Force T, Krause DS, and Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7:332-344.
48. Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, Racchumi J, Xu G, Wu H, and Ma J et al. (2014) Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med 370:2352-2354.
49. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, and Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876-880.
50. Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615-627.
51. Graham SM, Jørgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, and Holyoake TL (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99:319-325.
52. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, and Stevens C et al. (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153-158.
53. Hahn WC and Weinberg RA (2002) Modelling the molecular circuitry of cancer. Nat Rev Cancer 2:331-341.
54. Hall MD, Handley MD, and Gottesman MM (2009) Is resistance useless? Multidrug resistance and collateral sensitivity. Trends Pharmacol Sci 30:546-556.
55. Hall-Jackson CA, Goedert M, Hedge P, and Cohen P (1999) Effect of SB 203580 on the activity of c-Raf in vitro and in vivo. Oncogene 18:2047-2054.
56. Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70.
57. Hanks SK and Hunter T (1995) Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J 9:576-596.
58. Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, Hewitt JF, Zak M, Peck A, and Orr C et al. (2013) Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 501:232-236.
59. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, and Vigers G et al. (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464:431-435.
60. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, and Druker BJ et al. (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349.
61. Heinrich T, Grädler U, Böttcher H, Blaukat A, and Shutes A (2010) Allosteric IGF-1R Inhibitors. ACS Med Chem Lett 1:199-203.
62. Herbert C, Schieborr U, Saxena K, Juraszek J, De Smet F, Alcouffe C, Bianciotto M, Saladino G, Sibrac D, and Kudlinzki D et al. (2013) Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell 23:489-501.
63. Heymach JV, Nilsson M, Blumenschein G, Papadimitrakopoulou V, and Herbst R (2006) Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin Cancer Res 12:4441s-4445s.
64. Hill ZB, Perera BG, Andrews SS, and Maly DJ (2012) Targeting diverse signaling interaction sites allows the rapid generation of bivalent kinase inhibitors. ACS Chem Biol 7:487-495.
65. Hindie V, Stroba A, Zhang H, Lopez-Garcia LA, Idrissova L, Zeuzem S, Hirschberg D, Schaeffer F, Jørgensen TJ, and Engel M et al. (2009) Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat Chem Biol 5:758-764.
66. Holderfield M, Merritt H, Chan J, Wallroth M, Tandeske L, Zhai H, Tellew J, Hardy S, Hekmat-Nejad M, and Stuart DD et al. (2013) RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. Cancer Cell 23:594-602.
67. Holderfield M, Nagel TE, and Stuart DD (2014) Mechanism and consequences of RAF kinase activation by small-molecule inhibitors. Br J Cancer 111:640-645.
68. Hoy SM (2014) Ponatinib: a review of its use in adults with chronic myeloid leukaemia or Philadelphia chromosome-positive acute lymphoblastic leukaemia. Drugs 74:793-806.
69. Hsieh AC and Moasser MM (2007) Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 97:453-457.
70. Hunter T (2000) Signaling - 2000 and beyond. Cell 100:113-127.
71. Hynes NE and Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341-354.
72. Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, and Abraham R et al. (2004) Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 3:763-772.
73. Jahnke W, Grotzfeld RM, Pellé X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, and Mestan J et al. (2010) Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J Am Chem Soc 132:7043-7048.
74. Jänne PA, Gray N, and Settleman J (2009) Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 8:709-723.
75. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, and Barretina J et al. (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968-972.
76. Jura N, Zhang X, Endres NF, Seeliger MA, Schindler T, and Kuriyan J (2011) Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell 42:9-22.
77. Kannan N and Taylor SS (2008) Rethinking pseudokinases. Cell 133:204-205.
78. Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, and Halmos B et al. (2012). Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4:120-117.
79. Knapp S, Arruda P, Blagg J, Burley S, Drewry DH, Edwards A, Fabbro D, Gillespie P, Gray NS, and Kuster B et al. (2013) A public-private partnership to unlock the untargeted kinome. Nat Chem Biol 9:3-6.
80. Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, and Halmos B (2005) EGFR mutation and resistance of nonsmall-cell lung cancer to gefitinib. N Engl J Med 352:786-792.
81. Kornev AP, Haste NM, Taylor SS, and Eyck LF (2006) Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism. Proc Natl Acad Sci USA 103:17783-17788.
82. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, and Lynch TJ et al. (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665-7670.
83. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, and Tesar B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-620.
84. le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, and Gambacorti-Passerini C (2000) Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 95:1758-1766.
85. Lee KH, Hsu EC, Guh JH, Yang HC, Wang D, Kulp SK, Shapiro CL, and Chen CS (2011) Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. J Biol Chem 286:39247-39258.
86. Levitzki A (2003) Protein kinase inhibitors as a therapeutic modality. Acc Chem Res 36:462-469.
87. Li M, Youngren JF, Manchem VP, Kozlowski M, Zhang BB, Maddux BA, and Goldfine ID (2001) Small molecule insulin receptor activators potentiate insulin action in insulin-resistant cells. Diabetes 50:2323-2328.
88. Lin K, Lin J, Wu W-I, Ballard J, Lee BB, Gloor SL, Vigers GP, Morales TH, Friedman LS, and Skelton N et al. (2012) An ATP-site on-off switch that restricts phosphatase accessibility of Akt. Sci Signal 5:ra37.
89. Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, and Huber HE et al. (2005) Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett 15:761-764.
90. Liu Q, Sabnis Y, Zhao Z, Zhang T, Buhrlage SJ, Jones LH, and Gray NS (2013) Developing irreversible inhibitors of the protein kinase cysteinome. Chem Biol 20:146-159.
91. Liu Y and Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358-364.
92. Logue JS and Morrison DK (2012) Complexity in the signaling network: insights from the use of targeted inhibitors in cancer therapy. Genes Dev 26:641-650.
93. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, and Doweyko AM et al. (2004) Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4- ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658-6661.
94. Lopez-Garcia LA, Schulze JO, Fröhner W, Zhang H, Süss E, Weber N, Navratil J, Amon S, Hindie V, and Zeuzem S et al. (2011) Allosteric regulation of protein kinase PKCζ by the N-terminal C1 domain and small compounds to the PIF-pocket. Chem Biol 18:1463-1473.
95. Luo J, Solimini NL, and Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823-837.
96. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, and Melo JV (2003) MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101:2368-2373.
97. Manning G, Whyte DB, Martinez R, Hunter T, and Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912-1934.
98. Martiny-Baron G and Fabbro D (2007). Classical PKC isoforms in cancer. Pharmacol Res 55:477-486.
99. Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, Nehama D, Rajadas J, and Longo FM (2010) Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest 120:1774-1785.
100. Medina T, Amaria MN, and Jimeno A (2013) Dabrafenib in the treatment of advanced melanoma. Drugs Today (Barc) 49:377-385.
101. Mendoza MC, Er EE, and Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36:320-328.
102. Moebitz H and Fabbro D (2012) Conformational bias: a key concept for protein kinase inhibition. Eur Pharm Rev 17:41-51.
103. Motzer RJ, Hoosen S, Bello CL, and Christensen JG (2006) Sunitinib malate for the treatment of solid tumours: a review of current clinical data. Expert Opin Investig Drugs 15:553-561.
104. Noble ME, Endicott JA, and Johnson LN (2004) Protein kinase inhibitors: insights into drug design from structure. Science 303:1800-1805.
105. Nolen B, Taylor S, and Ghosh G (2004) Regulation of protein kinases; controlling activity through activation segment conformation. Mol Cell 15:661-675.
106. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, and Xu Q et al. (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401-412.
107. Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, and Banotai C et al. (2004) Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11:1192-1197.
108. Okuzumi T, Fiedler D, Zhang C, Gray DC, Aizenstein B, Hoffman R, and Shokat KM (2009) Inhibitor hijacking of Akt activation. Nat Chem Biol 5:484-493.
109. Olaharski AJ, Gonzaludo N, Bitter H, Goldstein D, Kirchner S, Uppal H, and Kolaja K (2009) Identification of a kinase profile that predicts chromosome damage induced by small molecule kinase inhibitors. PLOS Comput Biol 5:e1000446.
110. Over B, Wetzel S, Grütter C, Nakai Y, Renner S, Rauh D, and Waldmann H (2013) Natural-product-derived fragments for fragment-based ligand discovery. Nat Chem 5:21-28.
111. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, and Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73.
112. Pender C, Goldfine ID, Manchem VP, Evans JL, Spevak WR, Shi S, Rao S, Bajjalieh S, Maddux BA, and Youngren JF (2002) Regulation of insulin receptor function by a small molecule insulin receptor activator. J Biol Chem 277:43565-43571.
113. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, Shi H, Atefi M, Titz B, and Gabay MT et al. (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387-390.
114. Poulikakos PI, Zhang C, Bollag G, Shokat KM, and Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427-430.
115. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, and Bernards R (2012) Unresponsiveness of colon cancer to BRAF (V600E) inhibition through feedback activation of EGFR. Nature 483:100-103.
116. Quintás-Cardama A, Kantarjian H, and Cortes J (2007) Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov 6:834-848.
117. Rauch J, Volinsky N, Romano D, and Kolch W (2011) The secret life of kinases: functions beyond catalysis. Cell Commun Signal 9:23.
118. Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, Wechsler J, Lhomme C, Escudier B, and Boige V et al. (2005) Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491-500.
119. Rodon J, Dienstmann R, Serra V, and Tabernero J (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10:143-153.
120. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, and Rosen N (2011) mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov 1:248-259.
121. Rubin BP and Duensing A (2006) Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest 86:981-986.
122. Sadowsky JD, Burlingame MA, Wolan DW, McClendon CL, Jacobson MP, and Wells JA (2011) Turning a protein kinase on or off from a single allosteric site via disulfide trapping. Proc Natl Acad Sci USA 108:6056-6061.
123. Salt IP and Palmer TM (2012) Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation. Expert Opin Investig Drugs 21:1155-1167.
124. Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, and Carling D (2007) Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem 282:32539-32548.
125. Sawyers C (2004) Targeted cancer therapy. Nature 432:294-297.
126. Serra V, Scaltriti M, Prudkin L, Eichhorn PJA, Ibrahim YH, Chandarlapaty S, Markman B, Rodriguez O, Guzman M, and Rodriguez S et al. (2011) PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30:2547-2557.
127. Sharma SV and Settleman J (2010) Exploiting the balance between life and death: targeted cancer therapy and "oncogenic shock". Biochem Pharmacol 80:666-673.
128. She QB, Solit D, Basso A, and Moasser MM (2003) Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin Cancer Res 9:4340-4346.
129. Siegel R, Naishadham D, and Jemal A (2012) Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin 62:283-298.
130. Skora L, Mestan J, Fabbro D, Jahnke W, and Grzesiek S (2013) NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors. Proc Natl Acad Sci USA 110:E4437-E4445.
131. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, and Flaherty KT et al. (2012) RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366:207-215.
132. Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, and Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219-234.
133. Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, Yamamoto S, Nokihara H, Yamamoto N, and Sekine I et al. (2005) Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:6829-6837.
134. Tao ZF, Wang L, Stewart KD, Chen Z, Gu W, Bui MH, Merta P, Zhang H, Kovar P, and Johnson E et al. (2007) Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. J Med Chem 50:1514-1527.
135. Taylor SS and Kornev AP (2011) Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem Sci 36:65-77.
136. Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, and MacConaill L et al. (2007) High-throughput oncogene mutation profiling in human cancer. Nat Genet 39:347-351.
137. Tomita N, Hayashi Y, Suzuki S, Oomori Y, Aramaki Y, Matsushita Y, Iwatani M, Iwata H, Okabe A, and Awazu Y et al. (2013) Structure-based discovery of cellular-active allosteric inhibitors of FAK. Bioorg Med Chem Lett 23:1779-1785.
138. Trusolino L and Bertotti A (2012) Compensatory pathways in oncogenic kinase signaling and resistance to targeted therapies: six degrees of separation. Cancer Discov 2:876-880.
139. Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, and Sequist L et al. (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17:77-88.
140. Udugamasooriya DG, Dineen SP, Brekken RA, and Kodadek T (2008) A peptoid "antibody surrogate" that antagonizes VEGF receptor 2 activity. J Am Chem Soc 130:5744-5752.
141. Ventura JJ and Nebreda AR (2006) Protein kinases and phosphatases as therapeutic targets in cancer. Clin Transl Oncol 8:153-160.
142. Vieth M, Higgs RE, Robertson DH, Shapiro M, Gragg EA, and Hemmerle H (2004) Kinomics-structural biology and chemogenomics of kinase inhibitors and targets. Biochim Biophys Acta 1697:243-257.
143. Vieth M, Sutherland JJ, Robertson DH, and Campbell RM (2005) Kinomics: characterizing the therapeutically validated kinase space. Drug Discov Today 10:839-846.
144. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Jr, and Kinzler KW (2013) Cancer genome landscapes. Science 339:1546-1558.
145. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, and Hahn WC et al. (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29:3085-3096.
146. Wang X and Sun SY (2009) Enhancing mTOR-targeted cancer therapy. Expert Opin Ther Targets 13:1193-1203.
147. Weinstein IB (2002) Cancer. Addiction to oncogenes - the Achilles heal of cancer. Science 297:63-64.
148. Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, and Hall-Meyers E et al. (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129-141.
149. Wiestner A (2013) Targeting B-cell receptor signaling for anticancer therapy: the Bruton's tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies. J Clin Oncol 31:128-130.
150. Wolf-Yadlin A, Kumar N, Zhang Y, Hautaniemi S, Zaman M, Kim HD, Grantcharova V, Lauffenburger DA, and White FM (2006) Effects of HER2 overexpression on cell signaling networks governing proliferation and migration. Mol Syst Biol 2:54.
151. Wong KK, Engelman JA, and Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87-90.
152. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, and Lackey K et al. (2004) A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64:6652-6659.
153. Workman P, Al-Lazikani B, and Clarke PA (2013) Genome-based cancer therapeutics: targets, kinase drug resistance and future strategies for precision oncology. Curr Opin Pharmacol 13:486-496.
154. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD, and Panayotou G (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 16:1722-1733.
155. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, and Pavletich NP (2013) mTOR kinase structure, mechanism and regulation. Nature 497:217-223.
156. Yang J, Campobasso N, Biju MP, Fisher K, Pan XQ, Cottom J, Galbraith S, Ho T, Zhang H, and Hong X et al. (2011) Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site. Chem Biol 18:177-186.
157. Yarden Y and Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12:553-563.
158. Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, and Sun F et al. (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463:501-506.
159. Zhang J, Yang PL, and Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28-39.
160. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, and Padera R et al. (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462:1070-1074.
161. Zhou W, Ercan D, Jänne PA, and Gray NS (2011) Discovery of selective irreversible inhibitors for EGFR-T790M. Bioorg Med Chem Lett 21:638-643.
162. Zuccotto F, Ardini E, Casale E, and Angiolini M (2010) Through the "gatekeeper door": exploiting the active kinase conformation. J Med Chem 53:2681-2694.