In-silico approaches to multi-target drug discovery computer aided multi-target drug design, multi-target virtual screening

Pharmaceutical Research

Volumn 27, Issue 5, 2010, Pages 739-749

  Ma, Xiao Hua ^a   Shi, Zhe ^a   Tan, Chunyan ^b   Jiang, Yuyang ^b   Go, Mei Lin ^a   Low, Boon Chuan ^a   Chen, Yu Zong ^a  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b TSINGHUA UNIVERSITY   (China)

Author keywords

Computer aided dug design; Multi target; Multi target drug discovety; Multiple ligands; Virtual screening

Indexed keywords

1 [4 (3 AMINO 1H INDAZOL 4 YL)PHENYL] 3 (2 FLUORO 5 METHYLPHENYL)UREA; 6 (4 ETHYNYLPHENYL) 1,2,3,5,6,10B HEXAHYDROPYRROLO[2,1 A]ISOQUINOLINE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ANTIFUNGAL AGENT; ANTIINFECTIVE AGENT; ANTINEOPLASTIC AGENT; ANTIVIRUS AGENT; AST 487; CHIR 265; CLOMIPRAMINE; CUROUMIN; DASATINIB; DOVITINIB; DULOXETINE; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; FLAVOPIRIDOL; IMATINIB; IMIPRAMINE; JNJ 7706621; LAPATINIB; LEVODOPA; MOTESANIB; PAZOPANIB; ROSCOVITINE; SORAFENIB; SUNITINIB; SURAMIN; TANDUTINIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB;

ACUTE GRANULOCYTIC LEUKEMIA; BREAST CANCER; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; COLON CANCER; COLORECTAL CANCER; COMPUTER AIDED DESIGN; COMPUTER ANALYSIS; COMPUTER MODEL; DRUG DESIGN; DRUG EFFICACY; DRUG MECHANISM; DRUG RESEARCH; DRUG SAFETY; DRUG SCREENING; DRUG SYNTHESIS; DRUG TARGETING; GASTROINTESTINAL STROMAL TUMOR; HUMAN; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LIVER TUMOR; LUNG NON SMALL CELL CANCER; LUNG SMALL CELL CANCER; MACHINE LEARNING; MAJOR DEPRESSION; MELANOMA; MOLECULAR DOCKING; MULTIPLE MYELOMA; MYELOID LEUKEMIA; MYELOMA; NONHUMAN; NOTE; OVARY CANCER; PANCREAS CANCER; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN TARGETING; QUANTITATIVE STRUCTURE ACTIVITY RELATION; SOLID TUMOR; SUPPORT VECTOR MACHINE; THYROID CANCER;

ANIMALS; COMPUTER SIMULATION; COMPUTER-AIDED DESIGN; DRUG DESIGN; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; HUMANS; LIGANDS;

EID: 77953286121     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-010-0065-2     Document Type: Note

References (98)

1. Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT, Herlyn M. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther. 2006;5:1136-1144 (Pubitemid 43881305)
2. Pilpel Y, Sudarsanam P, Church GM. Identifying regulatoty networks by combinatorial analysis of promoter elements. Nat Genet. 2001;29:153-159 (Pubitemid 32952651)
3. Muller R. Crosstalk of oncogenic and prostanoid signaling pathways. J Cancer Res Clin Oncol. 2004;130:429-444 (Pubitemid 39119286)
4. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437-441 (Pubitemid 46160912)
5. Christopher M, Overall, Kleifeld O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6:227-239
6. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7:332-344 (Pubitemid 46652481)
7. Keith CT, Borisy AA, Stockwell BR. Multicomponent therapeutics for networked systems. Nat Rev Drug Discov. 2005;4:71-78
8. Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 1995;269:696-699
9. Zhang X, Crespo A, Fernandez A. Turning promiscuous kinase inhibitors into safer drugs. Trends Biotechnol. 2008;26:295-301.
10. Krug M, Hilgeroth A. Recent advances in the development of multi-kinase inhibitors. Mini Rev Med Chem. 2008;8:1312-1327
11. Gill AL, Verdonk M, Boyle RG, Taylor R. A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in. clinical development. Curr Top Med Chem. 2007;7:1408-1422 (Pubitemid 47471238)
12. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3:269-280 (Pubitemid 43731112)
13. Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res. 2007;5:203-220 (Pubitemid 46569773)
14. Kong A, Calleja V, Leboucher P, Harris A, Parker PJ, Larijani B. HER2 oncogenic function escapes EGFR tyrosine kinase inhibitors via activation of alternative HER receptors in breast cancer cells. PLoS One. 2008;3:e2881.
15. Millan MJ. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther. 2006;110:135-370.
16. Ma XH, Zheng CJ, Han LY, Xie B, Jia J, Cao ZW, et al. Synergistic therapeutic actions of herbal ingredients and their mechanisms from molecular interaction and network perspectives. Drug Discov Today. 2009;14:579-588
17. Jayanthi LD, Ramamoorthy S. Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. Aaps J. 2005;7:E728-38.
18. Kopin IJ. Monoamine oxidase and catecholamine metabolism. J Neural Transm Suppl. 1994;41:57-67.
19. Oechsner M, Buhmann C, Strauss J, Stuerenburg HJ. COMTinhibition increases serum levels of dihydroxyphenylacetic acid (DOPAC) in patients with advanced Parkinson's disease. J Neural Transm. 2002;109:69-75. (Pubitemid 34146590)
20. Matzen L, van Amsterdam C, Rautenberg W, Greiner HE, Halting J, Seyfried CA, et al. 5-HT reuptake inhibitors with 5HT (IB/ID) antagonistic activity: a new approach toward efficient antidepressants. J Med. Chem. 2000;43:1149-1157 (Pubitemid 30173740)
21. Melloni P, Garniel G, Delia Torre A, Bonsignori A, Buonamici M, Pozzi O, et al. Potential antidepressant agents, aryloxy-benzyl derivatives of ethanolamine and morpholine. Eur J Med Chem. 1984;19:235-242 (Pubitemid 14075597)
22. Jia J, Zhu F, Ma X, Cao Z, Li Y, Chen YZ. Mechanisms of drug combinations: interaction and network perspectives. Nat Rev Drug Discov. 2009;8:111-128
23. Jenwitheesuk E, Horst JA, Rivas KL, Van. Voorhis WC, Samudrala R. Novel paradigms for drug discovery: computational multitarget screening. Trends Pharmacol Sci. 2008;29:62-71.
24. Aluisio L, Lord B, Barbier AJ, Fraser IC, Wilson SJ, Boggs J, et al. In-vitro and. in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor. Eur J Pharmacol. 2008;587:1416.
25. Maiyanoff BE, McComsey DF, Gardocki JF, Shank RP, Costanzo MJ, Nortey SO, et al. Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships. J Med Chem. 1987;30:1433-1454
26. Sathornsumetee S, Reardon DA. Targeting multiple kinases in glioblastoma multiforme. Expert Opin Investig Drugs. 2009;1.8:27792.
27. Meyer RD, Sacks DB, Rahimi N. IQGAPl-dependent signaling pathway regulates endothelial cell proliferation and angiogenesis. PLoS One. 2008;3:e3848.
28. Ren JG, Li. Z, Sacks DB. IQGAPl modulates activation of BRaf. Proc Natl Acad Sci U S A. 2007;104:10465-10469
29. Briggs MW, Sacks DB. IQGAP proteins are integral components of cytoskeletal regulation. EMBO Rep. 2003;4:571-574
30. Li S. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008;49:19-26. (Pubitemid 351146878)
31. Bates RC, Goldsmith JD, Bachelder RE, Brown C, Shibuya M, Oettgen P, et al. Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. Curr Biol. 2003;13:1721-1727 (Pubitemid 37216251)
32. Gockel I, Moehler M, Frerichs K, Drescher D, Trinh TT, Duenschede F, et al, Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer. Oncol Rep. 2008;20:845-850
33. Shoichet BK. Virtual screening of chemical libraries. Nature. 2004;432:862-865
34. Ma XH, Wang R, Yang SY, Li ZR, Xue Y, Wei YC, et al. Evaluation of virtual screening performance of support vector machines trained by sparsely distributed active compounds. J Chem Inf Model 2008;48(6)1227-1237
35. Gozalbes R, Simon L, Froloff N, Sartori E, Monteils C, Baudelle R. Development and experimental validation of a docking strategy for the generation of kinase-targeted libraries. J Med Chem. 2008;51:3124-3132 (Pubitemid 351821873)
36. Deng XQ, Wang HY, Zhao YL, Xiang ML, Jiang PD, Cao ZX, et a!. Pharmacophore modelling and virtual screening for identification of new Aurora-A kinase inhibitors. Chem Biol Drug Des. 2008;71:533-539
37. Deanda F, Stewart EL, Reno MJ, Drewry DH. Kinase-targeted library design through the application of the PharmPrint methodology. J Chem Inf Model. 2008;48:2395-2403
38. Briem H, Gunther J. Classifying "kinase inhibitor-likeness" by using machine-learning methods. Chembiochem. 2005;6:558-566
39. Gundla R, Kazemi R, Sanam R, Muttineni R, Sarma JA, Dayam R, et al. Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: combined ligand and targetbased approach. J Med Chem. 2008;51:3367-3377 (Pubitemid 351874995)
40. Clemente JC, Govindasamy L, Madabushi A, Fisher SZ, Moose RE, Yowell CA, et al. Structure of the aspartic protease plasmepsin 4 from, the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor. Acta Crystallogr D Biol Crystallogr. 2006;62:246-252
41. Wei D, Jiang X, Zhou L, Chen. J, Chen Z, He C, et al. Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching. J Med Chem. 2008;51:7882-7888
42. Morphy R, Rankovic Z. The physicochemical challenges of designing multiple ligands. J Med Chem. 2006;49:4961-4970
43. Morphy R. The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds. J Med Chem. 2006;49:2969-2978
44. Vina D, Uriarte E, Orallo F, Gonzalez-Diaz H. Alignment-free prediction of a drug-target complex network based on parameters of drug connectivity and protein sequence of receptors. Mol Pharm. 2009;6:825-835
45. Prado-Prado FJ, Uriarte E, Borges F, Gonzalez-Diaz H. Multitarget spectral moments for QSAR and Complex Networks study of antibacterial drugs. Eur J Med Chem. 2009;44:4516-4521
46. Gonzalez-Diaz H, Prado-Prado FJ. Unified. QSAR and networkbased computational chemistry approach to antimicrobials, part 1: multispecies activity models for antifungals. J Comput Chem. 2008;29:656-667
47. Gonzalez-Diaz H, Prado-Prado FJ, Santana L, Uriarte E. Unify QSAR approach to antimicrobials. Part 1: predicting antifungal activity against different species. Bioorg Med. Chem. 2006;14:597380.
48. Prado-Prado FJ, Martinez de la Vega O, Uriarte E, Ubeira FM, Chou KC, Gonzalez-Diaz H. Unified. QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drugdrug complex networks. Bioorg Med Chem. 2009;17:569-575
49. Ma XH, Jia J, Zhu F, Xue Y, Li ZR, Chen YZ. Comparative analysis of machine learning methods in ligand-based virtual screening of large compound libraries. Comb Chem High Throughput Screen. 2009;12:344-357
50. Han LY, Ma XH, Lin HH, Jia J, Zhu F, Xue Y, et al, A support vector machines approach for virtual screening of active compounds of single and. multiple mechanisms from large libraries at an improved hit-rate and enrichment factor. J Mol Graph Model. 2008;26:1276-1286
51. Liu. XH, Ma XH, Tan CY, Jiang YY, Go ML, Low BC, et al. Virtual screening of Abl inhibitors from large compound libraries by support vector machines. J Chem Inf Model. 2009;49:2101-2110
52. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted, therapies. Science. 2007;318:287-290
53. Bender A, Jenkins JL, Glick M, Deng Z, Nettles JH, Davies JW. "Bayes affinity fingerprints" improve retrieval rates in virtual screening and define orthogonal bioactivity space: when are multitarget drugs a feasible concept? J Chem Inf Model. 2006;46:2445-2456
54. Givehchi A, Bender A, Glen RC. Analysis of activity space by fragment fingerprints, 2D descriptors, and multitarget dependent transformation of 2D descriptors. J Chem. Inf Model. 2006;46:1078-1083
55. Renner S, Derksen S, Radestock S, Morchen F. Maximum common binding modes (MCBM): consensus docking scoring using multiple ligand information and interaction fingerprints. J Chem Inf Model. 2008;48:319-332
56. Erhan D, L'Heureux JP, Yue SY, Bengio Y. Collaborative filtering on a family of biological targets. J Chem Inf Model. 2006;46:626-635
57. Dragos H, Gilles M, Alexandre V Predicting the predictability: a. unified approach to the applicability domain problem of QSAR models. J Chem Inf Model. 2009;49:1762-1776
58. Guiard BP, El Mansari M, Blier P. Prospect of a dopamine contribution in the next generation of antidepressant drugs: the triple reuptake inhibitors. Curr Drug Targets. 2009;10:1069-1154
59. Wong CI, Koh TS, Soo R, Hartono S, Thng CH, McKeegan E, et al. Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. J Clin Oncol. 2009;27:4718-4726
60. Shankar DB, Li J, Tapang P, Owen McCall J, Pease LJ, Dai Y, et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition, of FLT3 phosphorylation, and signaling in. acute myeloid leukemia. Blood. 2007;109:3400-3408
61. Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, et al. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006;5:1007-1013 (Pubitemid 43724601)
62. Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am. 2008;37:511-524 xi.
63. Lee CB, Socinski MA. Vascular endothelial growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: a review of recent clinical trials. Rev Recent Clin Trials. 2007;2:117-120 (Pubitemid 46773879)
64. Weisberg E, Roesel J, Bold G, Furet P, Jiang J, Cools J, et al. Antileukemic effects of the novel, mutant FLT3 inhibitor NVPAST487: effects on PKC412-sensitive and -resistant FLT3expressing cells. Blood. 2008;112:5161-5170
65. Akeno-Stuart N, Croyle M, Knauf JA, Malaguarnera R, Vitagliano D, Santoro M, et al. The RET kinase inhibitor NVPAST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res. 2007;67:6956-6964 (Pubitemid 47105543)
66. Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005;105:2941-2948 (Pubitemid 40446289)
67. Lopes de Menezes DE, Peng J, Garrett EN, Louie SG, Lee SH, Wiesmann M, et al. CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin Cancer Res. 2005;11:5281-91. (Pubitemid 41003717)
68. Lee SH, Lopes de Menezes D, Vora J, Harris A, Ye H, Nordahl L, et al. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth, factor receptor kinase inhibitor, in colon cancer models. Clin Cancer Res. 2005;11:3633-3641
69. Srivastava M. Phase I trial begins for CHIR-265, a new melanoma drug. J Drugs Dermatol. 2006;5:537-537
70. Cortes JE, Jones D, O'Brien S, Jabbour E, Ravandi F, Koller C, et al. Results of dasatinib therapy in patients with early chronicphase chronic myeloid leukemia. J Clin Oncol. 2010;28:398-404.
71. Yu EY, Wilding G, Posadas E, Gross M, Culine S, Massard C, et al. Phase II study of dasatinib in patients with metastatic castrationresistant prostate cancer. Clin Cancer Res. 2009;15:7421-7428
72. Konecny GE, Glas R, Dering J, Manivong K, Qi J, Finn RS, et al. Activity of the multikinase inhibitor dasatinib against ovarian cancer cells. Br J Cancer. 2009;101:1699-1708
73. Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y, et al. Comparison of imatinib, dasatinib, nilotinib and. INNO406 in imatinib-resistant cell lines. Leuk Res. 2008;32:980-983
74. Tsao AS, He D, Saigal B, Liu S, Lee JJ, Bakkannagari S, et al. Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion. Mol Cancer Ther. 2007;6:196272. (Pubitemid 47052486)
75. Okabe S, Tauchi T, Ohyashiki K. Characteristics of dasatiniband imatinib-resistant chronic myelogenous leukemia cells. Clin Cancer Res. 2008;14:6181-6186
76. Aklilu M, Kindler HL, Donehower RC, Mani S, Vokes EE. Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann Oncol. 2003;14:1.270-3. (Pubitemid 37039054)
77. Nitta N, Sonoda A, Seko A, Ohta S, Nagatani Y, Tsuchiya K, et al. A combination of cisplatin-eluting gelatin microspheres and flavopiridol enhances antitumour effects in a. rabbit VX2 liver tumour model. Br J Radiol. 2009.
78. Christian BA, Grever MR, Byrd JC, Lin TS. Flavopiridol in chronic lymphocytic leukemia: a. concise review. Clin Lymphoma Myeloma. 2009;9 Suppl 3:S179-85.
79. Carvajal RD, Tse A, Shah MA, Lefkowitz RA, Gonen M, Gilman-Rosen L, et al. A phase II study of flavopiridol (Alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer. Pancreatology. 2009;9:404-409
80. Parker BW, Kaur G, Nieves-Neira W, Taimi M, Kohlhagen G, Shimizu T, et al, Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood. 1998;91:458-465 (Pubitemid 28053367)
81. Senderowi.cz AM. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs. 1999;17:313-320
82. Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs. 2008;17:253-261 (Pubitemid 351578205)
83. Sloan B, Scheinfeld NS. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs. 2008;9:1324-1335
84. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, et al, Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with, potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007;6:2012-2021
85. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645-652 (Pubitemid 34815868)
86. Lopes LF, Bacchi CE. Imatinib treatment for gastrointestinal stromal tumor (GIST). J Cell Mol Med. 2009 doi:10.1111./j.15824934.2009.00983
87. Radujkovic A, Schad M, Topaly J, Veldwijk MR, Laufs S, Schultheis BS, et al. Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABLInhibition of P-glycoprotein function by 17-AAG. Leukemia. 2005;19:1198-1206 (Pubitemid 40946004)
88. Emanuel S, Rugg CA, Gruninger RH, Lin R, Fuentes-Pesquera A, Connolly PJ, et al. The in vitro and in vivo effects of JNJ7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res. 2005;65:9038-9046
89. Schwartz J. Current combination chemotherapy regimens for metastatic breast cancer. Am J Health Syst Pharm. 2009;66:S3-8.
90. McHugh LA, Kriajevska M, Mellon. JK, Griffiths TR. Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens-evidence of schedule-dependent synergy. Urology. 2007;69:390-394 (Pubitemid 46274953)
91. DeAngelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette RL, Klisovic RB, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. 2006;108:3674-3681
92. Corbin AS, Griswold IJ, La. Rosee P, Yee KW, Heinrich MC, Reimer CL, et al. Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. Blood. 2004;104:3754-3757 (Pubitemid 39564454)
93. Mohapatra S, Coppola D, Riker AI, Pledger WJ. Roscovitine inhibits differentiation and invasion in a three-dimensional skin reconstruction model of metastatic melanoma. Mol Cancer Res. 2007;5:145-151 (Pubitemid 46423995)
94. Gusani NJ, Jiang Y, Kimchi ET, Staveley-O'Carroll KF, Cheng H, Ajani JA. New pharmacological developments in the treatment of hepnatocellular cancer. Drugs. 2009;69:2533-2540
95. Kim S, Yazici YD, Calzada G, Wang ZY, Younes MN, Jasser SA, et al. Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in. nude mice. Mol Cancer Ther. 2007;6:1785-1792 (Pubitemid 46954055)
96. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of suni.ti.nib in. patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329-1338
97. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124
98. Bates D. ZD-6474. AstraZeneca. Curr Opin Investig Drugs. 2003;4:1468-1472