ALK and ROS1 as a joint target for the treatment of lung cancer: A review

Translational Lung Cancer Research

Volumn 2, Issue 2, 2013, Pages 72-86

  de la Bellacasa, Raimon Puig ^a   Karachaliou, Niki ^b   Estrada Tejedor, Roger ^a   Teixidó, Jordi ^a   Costa, Carlota ^b   Borrell, José I ^a  

^a INSTITUT QUÍMIC DE SARRIÀ   (Spain)

^b Unit for Cancer Research   (Spain)

Author keywords

Anaplastic lymphoma kinase (ALK); Drug design; Kinase inhibitors; Non small cell lung cancer; Proto oncogene tyrosine protein kinase ROS (ROS1)

Indexed keywords

ANAPLASTIC LYMPHOMA KINASE; ANAPLASTIC LYMPHOMA KINASE INHIBITOR; CRIZOTINIB; PROTEIN TYROSINE KINASE; ROS1 PROTEIN; UNCLASSIFIED DRUG;

ANTIPROLIFERATIVE ACTIVITY; CHROMOSOME REARRANGEMENT; COMPUTER AIDED DESIGN; DRUG POTENCY; DRUG SELECTIVITY; DRUG TARGETING; ENZYME INHIBITION; HUMAN; LUNG CANCER; NON SMALL CELL LUNG CANCER; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; SYSTEMATIC REVIEW;

EID: 84906556036     PISSN: 22186751     EISSN: 22264477     Source Type: Journal    
DOI: 10.3978/j.issn.2218-6751.2013.03.11     Document Type: Review

References (107)

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.
2. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-smallcell lung cancer. N Engl J Med 2002;346:92-8.
3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.
4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.
5. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703.
6. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6.
7. Zhang X, Zhang S, Yang X, et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer 2010;9:188.
8. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 2009;115:1723-33.
9. Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol 2010;17:889-97.
10. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007;131:1190-203.
11. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70.
12. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012;18:378-81.
13. Jun HJ, Johnson H, Bronson RT, et al. The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation. Cancer Res 2012;72:3764-74.
14. Ou SH, Tan J, Yen Y, et al. ROS1 as a 'druggable' receptor tyrosine kinase:lessons learned from inhibiting the ALK pathway. Expert Rev Anticancer Ther 2012;12:447-56.
15. Shaw AT, Camidge DR, Engelman JA, et al. Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. J Clin Oncol 2012;30:abstr 7508.
16. Gunby RH, Ahmed S, Sottocornola R, et al. Structural Insights into the ATP Binding Pocket of the Anaplastic Lymphoma Kinase by Site-Directed Mutagenesis, Inhibitor Binding Analysis, and Homology Modeling. J Med Chem 2006;49:5759-68.
17. Galkin AV, Melnick JS, Kim S, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A 2007;104:270-5.
18. Okamoto M, Kojima H, Saito N, et al. Virtual screening and further development of novel ALK inhibitors. Bioorg Med Chem 2011;19:3086-95.
19. Ott GR, Wells GJ, Thieu TV, et al. 2, 7-disubstitutedpyrrolo[ 2, 1-f][1, 2, 4]triazines:new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity. J Med Chem 2011;54:6328-41.
20. Berman HM, Westbrook J, Feng Z, et al. The Protein Data Bank. Nucleic Acids Res 2000;28:235-42.
21. Lee CC, Jia Y, Li N, et al. Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain. Biochem J 2010;430:425-37.
22. Bossi RT, Saccardo MB, Ardini E, et al. Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors. Biochemistry 2010;49:6813-25.
23. Park H, Chi O, Kim J, et al. Identification of novel inhibitors of tropomyosin-related kinase A through the structure-based virtual screening with homology-modeled protein structure. J Chem Inf Model 2011;51:2986-93.
24. Donella-Deana A, Marin O, Cesaro L, et al. Unique substrate specificity of anaplastic lymphoma kinase (ALK):development of phosphoacceptor peptides for the assay of ALK activity. Biochemistry 2005;44:8533-42.
25. Tartari CJ, Gunby RH, Coluccia AM, et al. Characterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase. J Biol Chem 2008;283:3743-50.
26. Epstein LF, Chen H, Emkey R, et al. The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase. J Biol Chem 2012;287:37447-57.
27. Bryan MC, Whittington DA, Doherty EM, et al. Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors. J Med Chem 2012;55:1698-705.
28. Lewis RT, Bode CM, Choquette DM, et al. The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer. J Med Chem 2012;55:6523-40.
29. Cui JJ, Tran-Dubé M, Shen H, et al. Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of MesenchymalEpithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK). J Med Chem 2011;54:6342-63.
30. Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 2011;19:679-90.
31. Baskaran C, Ramachandran M. Computational molecular docking studies on anticancer drugs. Asian Pac Trop Dis 2012;2:S734-S738.
32. Gingrich DE, Lisko JG, Curry MA, et al. Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase. J Med Chem 2012;55:4580-93.
33. Li R, Xue L, Zhu T, et al. Design and synthesis of 5-aryl-pyridone-carboxamides as inhibitors of anaplastic lymphoma kinase. J Med Chem 2006;49:1006-15.
34. Milkiewicz KL, Weinberg LR, Albom MS, et al. Synthesis and structure-activity relationships of 1, 2, 3, 4-tetrahydropyrido[2, 3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. Bioorg Med Chem 2010;18:4351-62.
35. Ardini E, Galvani A. ALK Inhibitors, a Pharmaceutical Perspective. Front Oncol 2012;2:17.
36. Breslin HJ, Lane BM, Ott GR, et al. Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2, 4, 8, 22-te traazatetracyclo[14.3.1.13, 7.19, 13]docosa-1(20), 3(22), 4, 6, 9(21), 10, 12, 16, 18-nonaene macrocycles. J Med Chem 2012;55:449-64.
37. Ott GR, Tripathy R, Cheng M, et al. Discovery of a Potent Inhibitor of Anaplastic Lymphoma Kinase with in Vivo Antitumor Activity. ACS Med Chem Lett 2010;1:493-8.
38. Mesaros EF, Burke JP, Parrish JD, et al. Novel 2, 3, 4, 5-tetrahydro-benzo[d]azepine derivatives of 2, 4-diaminopyrimidine, selective and orally bioavailable ALK inhibitors with antitumor efficacy in ALCL mouse models. Bioorg Med Chem Lett 2011;21:463-6.
39. Mesaros EF, Thieu TV, Wells GJ, et al. Strategies to mitigate the bioactivation of 2-anilino-7-aryl-pyrrolo[2, 1-f] [1, 2, 4]triazines:identification of orally bioavailable, efficacious ALK inhibitors. J Med Chem 2012;55:115-25.
40. Zificsak CA, Theroff JP, Aimone LD, et al. Methanesulfonamido-cyclohexylamine derivatives of 2, 4-diaminopyrimidine as potent ALK inhibitors. Bioorg Med Chem Lett 2011;21:3877-80.
41. Inoshita K, Ono Y, Emura T, et al. Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors. Bioorg Med Chem Lett 2011;21:3788-93.
42. Kinoshita K, Asoh K, Furuichi N, et al. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem 2012;20:1271-80.
43. Deng X, Wang J, Zhang J, et al. Discovery of 3, 5-Diamino-1, 2, 4-triazole Ureas as Potent Anaplastic Lymphoma Kinase Inhibitors. ACS Med Chem Lett 2011;2:379-84.
44. Slavish PJ, Price JE, Jiang Q, et al. Synthesis of an aryloxy oxo pyrimidinone library that displays ALK-selective inhibition. Bioorg Med Chem Lett 2011;21:4592-6.
45. Xie HZ, Lan H, Pan YL, et al. Identification of novel anaplastic lymphoma kinase (ALK) inhibitors using a common feature pharmacophore model derived from known ligands crystallized with ALK. Chem Biol Drug Des 2013;81:175-84.
46. Bresler SC, Wood AC, Haglund EA, et al. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci Transl Med 2011;3:108ra114.
47. Shiao H, Chiang NJ, Hsieh HP. Anaplastic Lymphoma Kinase (ALK) Inhibitors: New Cancer Breakthroughs for Lung Cancer. J Cancer Res Pract 2011;27:143-56.
48. Chemical Computing Group Inc.; Molecular Operating Environment (MOE), 2012.10;1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2012.
49. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:1734-9.
50. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17.
51. Bossi RT, Saccardo MB, Ardini E, et al. Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors. Biochemistry 2010;49:6813-25.
52. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 2011;108:7535-40.
53. Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 2011;71:6051-60.
54. Lu L, Ghose AK, Quail MR, et al. ALK mutants in the kinase domain exhibit altered kinase activity and differential sensitivity to small molecule ALK inhibitors. Biochemistry 2009;48:3600-9.
55. Sun HY, Ji FQ. A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK. Biochem Biophys Res Commun 2012;423:319-24.
56. Tripathy R, McHugh RJ, Ghose AK, et al. Pyrazolonebased anaplastic lymphoma kinase (ALK) inhibitors:control of selectivity by a benzyloxy group. Bioorg Med Chem Lett 2011;21:7261-4.
57. Gu TL, Deng X, Huang F, et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 2011;6:e15640.
58. Doebele RC, Camidge DR. Targeting ALK, ROS1, and BRAF kinases. J Thorac Oncol 2012;7:S375-S376.
59. Chin LP, Soo RA, Soong R, et al. Targeting ROS1 with anaplastic lymphoma kinase inhibitors:a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer. J Thorac Oncol 2012;7:1625-30.
60. El-Deeb IM, Park BS, Jung SJ, et al. Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett 2009;19:5622-6.
61. Peach ML, Tan N, Choyke SJ, et al. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. J Med Chem 2009;52:943-51.
62. McDermott U, Iafrate AJ, Gray NS, et al. Genomic Alterations of Anaplastic Lymphoma Kinase May Sensitize Tumors to Anaplastic Lymphoma Kinase Inhibitors. Cancer Res 2008;68:3389-95.
63. Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 2008;105:19893-7.
64. Wang YW, Tu P, Lin K, et al. Identification of oncogenic point mutations and hyperphosphorylation of anaplastic lymphoma kinase in lung cancer. Neoplasia 2011;13:704-15.
65. George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 2008;455:975-8.
66. Cerchietti L, Damm-Welk C, Vater I, et al. Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas. PLoS One 2011;6:e18436.
67. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A 2011;108:7535-40.
68. Duijkers FA, Gaal J, Meijerink JP, et al. Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels. Cell Oncol (Dordr) 2011;34:409-17.
69. Christensen JG, Zou HY, Arango ME, et al. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007;6:3314-22.
70. Zou HY, Li Q, Lee JH, et al. An Orally Available Small-Molecule Inhibitor of c-Met, PF-2341066, Exhibits Cytoreductive Antitumor Efficacy through Antiproliferative and Antiangiogenic Mechanisms. Cancer Res 2007;67:4408-17.
71. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 2011;29:abstr 2501.
72. Sasaki T, Okuda K, Zheng W, et al. The neuroblastomaassociated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010;70:10038-43.
73. Sasaki T, Rodig SJ, Chirieac LR, et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010;46:1773-80.
74. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-smallcell lung cancer harbouring ALK gene rearrangement:a retrospective analysis. Lancet Oncol 2011;12:1004-12.
75. Wang Y, Huang W, Liu S, et al. inventors. Ariad Pharmaceuticals I, USA, assignee. Preparation of phosphorus derivatives as kinase inhibitors. WO2009143389. Patent Application Date: May 21, 2009.
76. Shakespeare WC, Fantin VR, Wang F, et al. Discovery of potent and selective orally active inhibitors of anaplastic lymphoma kinase (ALK). American Association for cancer research annual meeting (AACR) 2009;abstr 3738.
77. Rivera VM, Anjum R, Wang F, et al. Efficacy and pharmacodynamic analysis of AP26113, a potent and selective orally active inhibitor of anaplastic lymphoma kinase (ALK). Cancer Res 2010;70:abstr 3623.
78. Zhang S, Wang F, Keats J, et al. AP26113, a potent ALK inhibitor, overcomes mutations in EML4-ALK that confer resistance to PF-02341066 (PF1066). Cancer Res 2010;70:abstr LB-298.
79. Lovly CM, Heuckmann JM, de Stanchina E, et al. Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase Inhibitors. Cancer Res 2011;71:4920-31.
80. Liang C, Li Z. inventors. Xcovery I, USA, assignee. Substituted pyridazine carboxamides as kinase inhibitors. WO2009154769. Patent Application Date: June 18, 2009.
81. Lovly CM, de Stanchina E, Liang C, et al. Preclinical development of a selective, potent small molecule ALK inhibitor. Cancer Res 2010;70:abstr 1788.
82. Xcovery. Targeted therapeutics. Available online: http://www.xcovery.com/alk (accessed Mar 13, 2013).
83. Kinoshita K, Kobayashi T, Asoh K, et al. 9-Substituted 6, 6-Dimethyl-11-oxo-6, 11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors. J Med Chem 2011;54:6286-94.
84. Sabbatini P, Korenchuk S, Rowand JL, et al. GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol Cancer Ther 2009;8:2811-20.
85. Chamberlain SD, Redman AM, Wilson JW, et al. Optimization of 4, 6-bis-anilino-1H-pyrrolo[2, 3-d] pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity. Bioorg Med Chem Lett 2009;19:360-4.
86. Kuromitsu S, Mori M, Shimada I, et al. Antitumor activities of ASP3026 against EML4-ALK-dependent tumor models. Mol Cancer Ther 2011;10:abstr A227.
87. Gunby RH, Tartari CJ, Porchia F, et al. An enzymelinked immunosorbent assay to screen for inhibitors of the oncogenic anaplastic lymphoma kinase. Haematologica 2005;90:988-90.
88. Wan W, Albom MS, Lu L, et al. Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells. Blood 2006;107:1617-23.
89. Ambrogio C, Martinengo C, Voena C, et al. NPMALK oncogenic tyrosine kinase controls T-Cell identity by transcriptional regulation and epigenetic silencing in lymphoma cells. Cancer Res 2009;69:8611-9.
90. Allwein SP, Roemmele RC, Haley JJ, et al. Development and Scale-Up of an Optimized Route to the ALK Inhibitor CEP-28122. Org Process Res Dev 2012;16:148-55.
91. Fancelli D, Moll J, Varasi M, et al. 1, 4, 5, 6-Tetrahydropyrrolo[3, 4-c]pyrazoles:Identification of a Potent Aurora Kinase Inhibitor with a Favorable Antitumor Kinase Inhibition Profile. J Med Chem 2006;49:7247-51.
92. Pulford K, Morris SW, Turturro F. Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol 2004;199:330-58.
93. Ardini E, Menichincheri M, Banfi P, et al. In vitro and in vivo activity of NMS-E628 against ALK mutations resistant to Xalkori. Mol Cancer Ther 2011;10:abstr A232.
94. Ardini E, Menichincheri M, De Ponti C, et al. Characterization of NMS-E628, a small molecule inhibitor of anaplastic lymphoma kinase with antitumor efficacy in ALK-dependent lymphoma and non-small cell lung cancer models. Mol Cancer Ther 2009;8:abstr A243.
95. Webb TR, Slavish J, George RE, et al. Anaplastic lymphoma kinase:role in cancer pathogenesis and smallmolecule inhibitor development for therapy. Expert Rev Anticancer Ther 2009;9:331-56.
96. Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 2012;30:abstr 3007.
97. Garcia-echeverria C, Kanazawa T, Kawahara E, et al. Inventors. Novartis A.-G. S, Novartis Pharma G.m.b.H. and IRM LLC, assignees. Preparation of 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders. WO2005016894. Patent Application Date: August 13, 2004.
98. Kruczynski A, Mayer P, Marchand A, et al. Antitumor activity of pyridoisoquinoline derivatives F91873 and F91874, novel multikinase inhibitors with activity against the anaplastic lymphoma kinase. Anti-Cancer Drugs 2009;20:364-72.
99. Tesaro. Pipeline. Available online: http://tesarobio.com/pipeline/(accessed Mar 13, 2013).
100. Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 2010;28:4953-60.
101. Chen Z, Sasaki T, Tan X, et al. Inhibition of ALK, PI3K/MEK, and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene. Cancer Res 2010;70:9827-36.
102. El-Hariry I, Proia D, Vukovic V. inventors. Synta Pharmaceuticals Corp. U, assignee. Treating cancer with heat-shock protein-90 (HSP90) inhibitory compounds such as ganetespib. WO2013006864. Patent Application Date:July 9, 2012.
103. El-Deeb IM, Yoo KH, Lee SH. ROS receptor tyrosine kinase:a new potential target for anticancer drugs. Med Res Rev 2010;31:794-818.
104. Araman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127-32.
105. Banerjee P. Recognition of c-ROS oncogene inhibition with a FRET-based receptor construct. MURJ 2004;10:52-7.
106. Park BS, El-Deeb IM, Yoo KH, et al. Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor. Bioorg Med Chem Lett 2009;19:4720-3.
107. Park BS, El-deeb IM, Yoo KH, et al. Synthesis and biological activity of new 4-(pyridin-4-yl)-(3-methoxy-5-methylphenyl)-1H-pyrazoles derivatives as ROS receptor tyrosine kinase inhibitors. Bull Korean Chem Soc 2012;33:3629-34.