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Identification of Potential Off-Targets of Chemotherapeutic Agent Sorafenib: A Molecular Docking Approach

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Abstract:

B-Raf is a multi- drug target serine/threonine protein kinase, involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Mutated B-Raf causes overactive downstream signaling via MEK and ERK, leading to excessive cell proliferation and survival, independent of growth factors causing cancers such as Pancreatic carcinoma. A novel bi-aryl urea- Sorafenib, is a potent inhibitor of Raf-1 that has been approved for the treatment of a number of cancers including pancreatic cancer. The present investigation was designed to identify the potential off-targets of Sorafenib which could be responsible for its reported undesirable side effects. Molecular docking was used to test the efficacy of structural analogs of Sorafenib against B-Raf using FlexX and it was found that the analog with CID:10151557 had a high potency with minimum number of clashes, low lipophilic score and high match score, similar to Sorafenib. To identify the potential off-target/s of Sorafenib, macromolecular surface similarity detection software MEDIT SA MED-SuMo was used and the results obtained were validated through literature. The possible off-targets obtained belonged to the family of protein tyrosine kinases i.e. VEGFR-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT, each of which were docked with Sorafenib. Based on high docking scores and similarity with B-Raf for its binding site interacting residues, it was concluded that Vascular endothelial growth factor tyrosine kinase receptor (VEGFR) is a potential off-target of anti-cancer chemotherapeutic agent Sorafenib.

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Periodical:

International Letters of Natural Sciences (Volume 51)

Pages:

51-57

DOI:

https://doi.org/10.56431/p-q473hz

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Online since:

February 2016

Authors:

Tammanna R. Sahrawat, Parul Chawla

Keywords:

Cancer, Chemotherapeutic Agent, Drug Off-Targets, Molecular Docking, Receptor Tyrosine Kinases, Sorefenib

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References

[1] J. Ling, Y. Kang, R. Zhao, Q. Xia, D.F. Lee , Z. Chang, J. Li , B. Peng, J.B. Fleming, H. Wang, J. Liu, I.R. Lemischka, M.C. Hung, P.J. Chiao, Kras (G12D)-Induced IKK2/β/NF-κB Activation by IL-1α and p.62 Feed forward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma. Cancer Cell 21[2012] 105-20.

DOI: 10.1016/j.ccr.2011.12.006

Google Scholar

[2] D. Singh, G. Upadhyay, R.K. Srivastava, S. Shanker, Recent advances in pancreatic cancer:biology, treatment and prevention, Biochimica et Biophysica Acta (BBA)- Reviews on Cancer 1856[1] (2015) 12-27.

DOI: 10.1016/j.bbcan.2015.04.003

Google Scholar

[3] L. Liu, Y. Cao, C. Chen, X. Zhang, A. McNabola, D. Wilkie, S. Wilhelm, M. Lynch, C. Carter, Sorafenib Blocks the RAF/MEK/ERK Pathway, Inhibits Tumor Angiogenesis, and Induces Tumor Cell Apoptosis in Hepatocellular Carcinoma Model PLC/PRF/5, Cancer Res. 66 (2006) 11851.

DOI: 10.1158/0008-5472.can-06-1377

Google Scholar

[4] M. Karbowniczek, G.P. Robertson, E.P. Henske, Rheb Inhibits C-Raf Activity and B-Raf/C-Raf Heterodimerization, The Journal of Biological Chemistry, 281(2006) 25447-25456.

DOI: 10.1074/jbc.m605273200

Google Scholar

[5] P.T.C Wan, M.J. Garnett, S.M. Roe, S. Lee, D. Niculescu-Duvaz, V.M. Good, C.M. Jones, C.J. Marshall, C.J. Springer, D. Barford, R. Marais; Cancer Genome Project, Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF, Cell 116[6] (2004) 855-867.

DOI: 10.1016/s0092-8674(04)00215-6

Google Scholar

[6] S. Benlloch, A. Paya, C. Alenda, X. Bessa, M. Andreu, R. Jover, A. Castells, X. Llor, F.I. Aranda, B. Massutí, Detection of BRAF V600E mutation in colorectal cancer: comparison of automatic sequencing and real-time chemistry methodology, J. Mol. Diagn. 8 [5] (2006) 540–3.

DOI: 10.2353/jmoldx.2006.060070

Google Scholar

[7] Y.H. Tan, Y. Liu, K.W. Eu, P.W. Ang, W.Q. Li, M. Salto-Tellez, B. Iacopetta, R. Soong, Detection of BRAF V600E mutation by pyrosequencing, Pathology 40[3] (2008) 295–8.

DOI: 10.1080/00313020801911512

Google Scholar

[8] M.H. Chen, R. Kerkelä, T. Force, Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics, Circulation 118 (2008) 84-95.

DOI: 10.1161/circulationaha.108.776831

Google Scholar

[9] G. Sithanandam, W. Kolch, F.M. Duh, U.R. Rapp, Complete coding sequence of a human B-Raf cDNA and detection of B- Raf protein kinase with isozyme specific antibodies, Oncogene 5[12] (1990) 1775–80.

Google Scholar

[10] M.N. Stein and K.T. Flaherty, CCR drug updates: Sorafenib and sunitib in renal cell carcinoma. Clin. Cancer Res. 13 (2007) 3765-3770.

DOI: 10.1158/1078-0432.ccr-06-2844

Google Scholar

[11] S. Cascinu, R. Berardi, A. Sobrero, P. Bidoli, R. Labianca, S.Siena, D. Ferrari, S. Barni, E.Aitini, V. Zagonel, F. Caprioni, F. Villa, S. Mosconi, L. Faloppi, G. Tonini, C. Boni, P. Conte, F.D. Costanzo, Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study, Digestive and Liver Disease 46[2] (2014) 182-186.

DOI: 10.1016/j.dld.2013.09.020

Google Scholar

[12] O. Abdel-Rahman and M. Fouad, Sorafenib-based combination as a first line of treatment fot advanced hepatocellular carcinoma: A systematic review of the literature, Clinical Reviews in Oncology/Hematology 91[1] (2014) 1-8.

DOI: 10.1016/j.critrevonc.2013.12.013

Google Scholar

[13] J.A. Gollob, S. Wilhelm, C. Carter, S.L. Kelley, Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway, Seminars in oncology 33[4] (2006) 392-406.

DOI: 10.1053/j.seminoncol.2006.04.002

Google Scholar

[14] H. Namba, M. Nakashima, T. Hayashi, N. Hayashida, S. Maeda, T.I. Rogounovitch, A. Ohtsuru, V.A. Saenko, T. Kanematsu, S. Yamashita, Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers, J. Clin. Endocrinol. Metab. 88[9] (2003) 4393–7.

DOI: 10.1210/jc.2003-030305

Google Scholar

[15] T. Ahmad and T. Eisen, Kinase inhibition with BAY 43-9006 in renal cell carcinoma, Clin. Cancer Res. 10 (2004) 6388-92.

DOI: 10.1158/1078-0432.ccr-040028

Google Scholar

[16] J. Tsai, J.T. Lee, W. Wang, J. Zhang, H. Cho, S. Mamo, R. Bremer, S. Gillette, J. Kong, N.K. Haass, K. Sproesser, L. Li, K.S. Smalley, D. Fong, Y.L. Zhu, A. Marimuthu, H. Nguyen, B. Lam, J. Liu, I. Cheung, J. Rice, Y. Suzuki, C. Luu, C. Settachatgul, R. Shellooe, J. Cantwell, S.H. Kim, J. Schlessinger, K.Y. Zhang, B.L. West, B. Powell, G. Habets, C. Zhang, P.N. Ibrahim, P. Hirth, D.R. Artis, M. Herlyn, G. Bollag, Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity, Proc. Natl. Acad. Sci. U.S.A. 105[8] (2008) 3041–6.

DOI: 10.1073/pnas.0711741105

Google Scholar

[17] M.J. Garnett and R. Marais, Guilty as charged: B-Raf is a human oncogene, Cancer Cell 6[4] (2004) 313–9.

Google Scholar

[18] J.L. Maldonado, J. Fridlyand, H. Patel, A. N. Jain, K. Busam, T. Kageshita, T. Ono, D.G. Albertson, D. Pinkel, B.C. Bastian, Determinants of BRAF mutations in primary melanomas, J. Natl. Cancer Inst. 95 [24] (2003)1878–90.

DOI: 10.1093/jnci/djg123

Google Scholar

[19] H. Davies, G.R. Bignell, C. Cox, P. Stephens, S. Edkins, S. Clegg, J. Teague, H. Woffendin, M.J. Garnett, W. Bottomley, N. Davis, E. Dicks, R. Ewing, Y. Floyd, K. Gray, S. Hall, R. Hawes, J. Hughes, V. Kosmidou, A. Menzies, C. Mould, A. Parker, C. Stevens, S. Watt, S. Hooper, R. Wilson, H. Jayatilake, B.A. Gusterson, C. Cooper, J. Shipley, D. Hargrave, K. Pritchard-Jones, N. Maitland, G. Chenevix-Trench, G.J. Riggins, D.D. Bigner, G. Palmieri, A. Cossu, A. Flanagan, A. Nicholson, J.W. Ho, S.Y. Leung, S.T. Yuen, B.L. Weber, H.F. Seigler, T.L. Darrow, H. Paterson, R. Marais, C.J. Marshall, R. Wooster, M.R. Stratton, P.A. Futreal, Mutations of the BRAF gene in human cancer, Nature 417 (2002) 949–54.

DOI: 10.1038/nature00766

Google Scholar

[20] A.J. King, D.R. Patrick, R.S. Batorsky, M.L. Ho, H.T. Do, S.Y. Zhang, R. Kumar, D.W. Rusnak, A.K. Takle, D.M. Wilson, E. Hugger, L. Wang, F. Karreth, J.C. Lougheed, J.Lee, D. Chau, T.J. Stout, E.W. May, C.M. Rominger, M.D. Schaber, L. Luo, A.S. Lakdawala, J.L. Adams, R.G. Contractor, K.S. Smalley, M. Herlyn, M.M. Morrissey, D.A. Tuveson, P.S. Huang, Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 66[23] (2006) 11100–5.

DOI: 10.1158/0008-5472.can-06-2554

Google Scholar

[21] H. Gear, H. Williams, E.G. Kemp, F. Roberts, BRAF mutations in conjunctival melanoma, Invest. Ophthalmol. Vis. Sci. 45[8] (2004) 2484–8.

DOI: 10.1167/iovs.04-0093

Google Scholar

[22] E. Puxeddu, S. Moretti, R. Elisei, C. Romei, R. Pascucci, M. Martinelli, C. Marino, N. Avenia, E.D. Rossi, G. Fadda, A. Cavaliere, R. Ribacchi, A. Falorni, A. Pontecorvi, F. Pacini, A. Pinchera, E. Santeusanio, BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas, J. Clin. Endocrinol. Metab. 89[5] (2004) 2414–20.

DOI: 10.1210/jc.2003-031425

Google Scholar

[23] A. Jayanthan, D. Bernoux, P. Bose, K. Riabowol, A. Narendran, Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition, Cancer Cell International, 11 (2011) 44.

DOI: 10.1186/1475-2867-11-44

Google Scholar

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