- Volume 16 Issue 16
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High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma
Dunna, Nageswara Rao;Kandula, Venkatesh;Girdhar, Amandeep;Pudutha, Amareshwari;Hussain, Tajamul;Bandaru, Srinivas;Nayarisseri, Anuraj
- Published : 2015.11.04
Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGNPC- 0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.
Medullary thyroid carcinoma;RET;VEGFR2;dual inhibitors;virtual screening
- Bandaru S, Ponnala D, Lakkaraju C, et al (2014). Identification of high affinity non-peptidic small molecule inhibitors of MDM2-p53 interactions through structure-based virtual screening strategies. Asian Pac J Cancer Prev, 16, 3759-3765.
- Bandaru S, Tiwari G, Akka J, et al (2015). Identification of high affinity bioactive salbutamol conformer directed against mutated (Thr164Ile) beta 2 adrenergic receptor. Cur Top Med Chem, 15, 50-6. https://doi.org/10.2174/1568026615666150112113040
- Brierley JD, Tsang R, Simpson WJ, et al. (1996) Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid, 6, 305-10. https://doi.org/10.1089/thy.1996.6.305
- Brozzo MS, Bjelić S, Kisko K, et al (2012). Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization. Blood, 119, 1781-8. https://doi.org/10.1182/blood-2011-11-390922
- Bunone G, Vigneri P, Mariani L, et al (1999). Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with pathological features. Am J Pathol, 155, 1967-76 https://doi.org/10.1016/S0002-9440(10)65515-0
- Cheng F, Li W, Zhou Y, et al (2012). AdmetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model, 52, 3099-105. https://doi.org/10.1021/ci300367a
- DeSantis CE, Lin CC, Mariotto AB, et al (2014). Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin, 64, 252-71. https://doi.org/10.3322/caac.21235
- Gilliland FD, Hunt WC, Morris DM, Key CR (1997). Prognostic factors for thyroid carcinoma: a population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program, 1973-1991. Cancer, 79, 564-73. https://doi.org/10.1002/(SICI)1097-0142(19970201)79:3<564::AID-CNCR20>3.0.CO;2-0
- Hundahl SA, Fleming ID, Fremgen AM, Menck HR (1996). A national cancer database report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995. Cancer, 83, 2638-48.
- Jorgensen WL, Maxwell DS & Tirado-Rives J (1996). Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc, 118, 11225-36. https://doi.org/10.1021/ja9621760
- Kelotra S, Jain M, Kelotra A., Jain I, et al (2014). An in silico appraisal to identify high affinity anti-apoptotic synthetic tetrapeptide inhibitors targeting the mammalian caspase 3 enzyme. Asian Pac J Cancer Prev, 15, 10137.
- Kilfoy BA, Zheng T, Holford TR, et al (2009). International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control, 20, 525-31. https://doi.org/10.1007/s10552-008-9260-4
- Knowles PP, Murray-Rust, et al (2006). Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem, 281, 33577-87. https://doi.org/10.1074/jbc.M605604200
- LigPrep, V. (2010). 2.4: Schrodinger. LLC, New York.
- Marsh DJ, Learoyd DL, Robinson BG (1995). Medullary thyroid carcinoma: recent advances and managment update. Thyroid, 5, 407-20 https://doi.org/10.1089/thy.1995.5.407
- Masbi MH, Mohammadiasl J, et al (2014). Characterization of wild-type and mutated RET proto-oncogene associated with familial medullary thyroid cancer. Asian Pac J Cancer Prev, 15, 2027-33. https://doi.org/10.7314/APJCP.2014.15.5.2027
- Maunz A, Gütlein M, Rautenberg M, et al (2013). Lazar: a modular predictive toxicology framework. Front Pharmacol, 4, 38.
- Mitsiades CS, et al (2006). Epidermal growth factor receptor as a therapeutic target in human thyroid carcinoma: mutational and functional analysis. J Clin Endocrinol Metab, 91, 3662-6 https://doi.org/10.1210/jc.2006-0055
- Nelder JA & Mead R (1965). A simplex method for function minimization. Comput J, 7, 308-13. https://doi.org/10.1093/comjnl/7.4.308
- Petrangolini G, Cuccuru G, Lanzi C, et al (2006). Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1. Biochem Pharmacol, 72, 405-14 https://doi.org/10.1016/j.bcp.2006.05.002
- Rougier P, Parmentier C, Laplanche A, et al (1983). Medullary thyroid carcinoma: prognostic factors and treatment. Int J Radiat Oncol Biol Phys, 9, 161-9 https://doi.org/10.1016/0360-3016(83)90093-7
- Samaan GA, Schultz PN, Hickey RC (1988). Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab, 67, 801-5. https://doi.org/10.1210/jcem-67-4-801
- Santoro M and Carlomagno F (2006). Drug Insight: smallmolecule inhibitors of protein kinases in the treatment of thyroid cancer. Nat Clin Pract Endocrinol Metab, 2, 42-52 https://doi.org/10.1038/ncpendmet0073
- Schlumberger M, Carlomagno F, et al (2008). New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab, 4, 22-32. https://doi.org/10.1038/ncpendmet0717
- Thomsen R & Christensen MH (2006). MolDock: a new technique for high-accuracy molecular docking. J Med Chem, 49, 3315-21. https://doi.org/10.1021/jm051197e
- Yeganeh MZ, Sheikholeslami S, & Hedayati M. (2015). RET proto oncogene mutation detection and medullary thyroid carcinoma prevention. Asian Pac J Cancer Prev, 16, 2107. https://doi.org/10.7314/APJCP.2015.16.6.2107
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- Novel targeted therapeutics for MEN2 vol.25, pp.2, 2018, https://doi.org/10.1530/ERC-17-0297
- Isomangiferin, a Novel Potent Vascular Endothelial Growth Factor Receptor 2 Kinase Inhibitor, Suppresses Breast Cancer Growth, Metastasis and Angiogenesis vol.21, pp.1, 2018, https://doi.org/10.4048/jbc.2018.21.1.11