3D-QSAR Studies on 4,5-Dihydro-1H-pyrazolo [4,3-h] Quinazolines as Plk-1, CDK2/A and Aur-A Serine/Threonine Kinase Inhibitors

Author(s): Bhoomendra A. Bhongade*, Nikhil D. Amnerkar*, Andanappa K. Gadad.

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 4 , 2020

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Graphical Abstract:


Background: The family of serine/threonine protein kinases is associated with peculiar tumor cell-cycle checkpoints which are overexpressed in proliferating tissues as well as in cancers, making them as potential targets for cancer chemotherapy. In the present paper, 3D-QSAR studies were carried out on 4,5-dihydro-1H-pyrazolo[4,3-h]quinazolines against serine/threonine protein kinases viz. polo-like 1 (Plk-1), cyclin dependent 2/A (CDK2/A) and Aurora-A (Aur-A) and their in vitro anti-proliferative activity on A2780 ovarian cancer cell line.

Methods: 3D-QSAR models were derived using stepwise forward-backward partial least square (SWFB_PLS) regression method using VlifeMDS QSAR plus software and the docking calculations were carried out using Docking Server.

Results: The derived statistically significant and predictive 3D-QSAR models exhibited correlation coefficient r2 in the range of 0.875 to 0.966 and predictive r2 in the range of 0.492 to 0.618. The hydrogen bond donor NH group joining the phenyl ring with quinazoline and terminal amide group were found to favored for Plk-1, CDK2/A and anti-proliferative activity. Estimated energy of binding of compound 45 with enzymes was in the range of -8.52 to -9.03.

Conclusion: The results of 3D-QSAR studies may be useful in the development of new pyrazolo[ 4,3-h]quinazoline derivatives with better inhibitory activities against serine/threonine kinases.

Keywords: 3D-QSAR, 4, 5-Dihydro-1H-pyrazolo [4, 3-h] quinazoline, kinase inhibitors, Plk-1, CDK2/A, Aur-A, serine/ threonine protein kinase.

Van Vuuren, R.J.; Visagie, M.H.; Theron, A.E.; Joubert, A.M. Antimitotic drugs in the treatment of cancer. Cancer Chemother. Pharmacol., 2015, 76(6), 1101-1112.
[http://dx.doi.org/10.1007/s00280-015-2903-8] [PMID: 26563258]
Fischer, P.M.; Glover, D.M.; Lane, D.P. Targeting the cell cycle. Drug Discov. Today Ther. Strateg., 2004, 1(4), 417-423.
Adams, R.R.; Carmena, M.; Earnshaw, W.C. Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol., 2001, 11(2), 49-54.
[http://dx.doi.org/10.1016/S0962-8924(00)01880-8] [PMID: 11166196]
Nigg, E.A. Mitotic kinases as regulators of cell division and its checkpoints. Nat. Rev. Mol. Cell Biol., 2001, 2(1), 21-32.
[http://dx.doi.org/10.1038/35048096] [PMID: 11413462]
Fu, J.; Bian, M.; Jiang, Q.; Zhang, C. Roles of aurora kinases in mitosis and tumorigenesis. Mol. Cancer Res., 2007, 5(1), 1-10.
[http://dx.doi.org/10.1158/1541-7786.MCR-06-0208] [PMID: 17259342]
Warner, S.L.; Bearss, D.J.; Han, H.; Von Hoff, D.D. Targeting aurora-2 kinase in cancer. Mol. Cancer Ther., 2003, 2(6), 589-595.
[PMID: 12813139]
Gautschi, O.; Heighway, J.; Mack, P.C.; Purnell, P.R.; Lara, P.N., Jr; Gandara, D.R. Aurora kinases as anticancer drug targets. Clin. Cancer Res., 2008, 14(6), 1639-1648.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-2179] [PMID: 18347165]
Sausville, E.A. Aurora kinases dawn as cancer drug targets. Nat. Med., 2004, 10(3), 234-235.
[http://dx.doi.org/10.1038/nm0304-234] [PMID: 14991042]
Krystof, V.; Uldrijan, S. Cyclin-dependent kinase inhibitors as anticancer drugs. Curr. Drug Targets, 2010, 11(3), 291-302.
[http://dx.doi.org/10.2174/138945010790711950] [PMID: 20210754]
Harper, J.W.; Adams, P.D. Cyclin-dependent kinases. Chem. Rev., 2001, 101(8), 2511-2526.
[http://dx.doi.org/10.1021/cr0001030] [PMID: 11749386]
Malumbres, M. Cyclin-dependent kinases. Genome Biol., 2014, 15(6), 122.
[http://dx.doi.org/10.1186/gb4184] [PMID: 25180339]
Shapiro, G.I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol., 2006, 24(11), 1770-1783.
[http://dx.doi.org/10.1200/JCO.2005.03.7689] [PMID: 16603719]
Sánchez-Martínez, C.; Gelbert, L.M.; Lallena, M.J.; de Dios, A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg. Med. Chem. Lett., 2015, 25(17), 3420-3435.
[http://dx.doi.org/10.1016/j.bmcl.2015.05.100] [PMID: 26115571]
Liu, X. Targeting polo-like kinases: A promising therapeutic approach for cancer treatment. Transl. Oncol., 2015, 8(3), 185-195.
[http://dx.doi.org/10.1016/j.tranon.2015.03.010] [PMID: 26055176]
Lee, S.Y.; Jang, C.; Lee, K.A. Polo-like kinases (plks), a key regulator of cell cycle and new potential target for cancer therapy. Dev. Reprod., 2014, 18(1), 65-71.
[http://dx.doi.org/10.12717/DR.2014.18.1.065] [PMID: 25949173]
Degenhardt, Y.; Lampkin, T. Targeting polo-like kinase in cancer therapy. Clin. Cancer Res., 2010, 16(2), 384-389.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1380] [PMID: 20068088]
Gross, S.; Rahal, R.; Stransky, N.; Lengauer, C.; Hoeflich, K.P. Targeting cancer with kinase inhibitors. J. Clin. Invest., 2015, 125(5), 1780-1789.
[http://dx.doi.org/10.1172/JCI76094] [PMID: 25932675]
Bhongade, B.A.; Gouripur, V.V.; Gadad, A.K. 3D-QSAR CoMFA studies on trypsin-like serine protease inhibitors: A comparative selectivity analysis. Bioorg. Med. Chem., 2005, 13(8), 2773-2782.
[http://dx.doi.org/10.1016/j.bmc.2005.02.027] [PMID: 15781388]
Beria, I.; Ballinari, D.; Bertrand, J.A.; Borghi, D.; Bossi, R.T.; Brasca, M.G.; Cappella, P.; Caruso, M.; Ceccarelli, W.; Ciavolella, A.; Cristiani, C.; Croci, V.; De Ponti, A.; Fachin, G.; Ferguson, R.D.; Lansen, J.; Moll, J.K.; Pesenti, E.; Posteri, H.; Perego, R.; Rocchetti, M.; Storici, P.; Volpi, D.; Valsasina, B. Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors. J. Med. Chem., 2010, 53(9), 3532-3551.
[http://dx.doi.org/10.1021/jm901713n] [PMID: 20397705]
Beria, I.; Valsasina, B.; Brasca, M.G.; Ceccarelli, W.; Colombo, M.; Cribioli, S.; Fachin, G.; Ferguson, R.D.; Fiorentini, F.; Gianellini, L.M.; Giorgini, M.L.; Moll, J.K.; Posteri, H.; Pezzetta, D.; Roletto, F.; Sola, F.; Tesei, D.; Caruso, M. 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazolines as potent and selective Polo-like kinase 1 (PLK1) inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(22), 6489-6494.
[http://dx.doi.org/10.1016/j.bmcl.2010.09.060] [PMID: 20932759]
Traquandi, G.; Ciomei, M.; Ballinari, D.; Casale, E.; Colombo, N.; Croci, V.; Fiorentini, F.; Isacchi, A.; Longo, A.; Mercurio, C.; Panzeri, A.; Pastori, W.; Pevarello, P.; Volpi, D.; Roussel, P.; Vulpetti, A.; Brasca, M.G. Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors. J. Med. Chem., 2010, 53(5), 2171-2187.
[http://dx.doi.org/10.1021/jm901710h] [PMID: 20141146]
Beria, I.; Bossi, R.T.; Brasca, M.G.; Caruso, M.; Ceccarelli, W.; Fachin, G.; Fasolini, M.; Forte, B.; Fiorentini, F.; Pesenti, E.; Pezzetta, D.; Posteri, H.; Scolaro, A.; Re Depaolini, S.; Valsasina, B. NMS-P937, a 4,5-dihydro-1H-pyrazolo [4,3-h] quinazoline derivative as potent and selective polo-like kinase 1 inhibitor. Bioorg. Med. Chem. Lett., 2011, 21(10), 2969-2974.
[http://dx.doi.org/10.1016/j.bmcl.2011.03.054] [PMID: 21470862]
Zhao, H.; Hu, X.; Cao, K.; Zhang, Y.; Zhao, K.; Tang, C.; Feng, B. Synthesis and SAR of 4,5-dihydro-1H-pyrazolo [4,3-h] quinazoline derivatives as potent and selective CDK4/6 inhibitors. Eur. J. Med. Chem., 2018, 157, 935-945.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.043] [PMID: 30165341]
Ai, Y.; Wang, S-T.; Sun, P-H.; Song, F-J. Molecular modeling studies of 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline derivatives as potent CDK2/Cyclin a inhibitors using 3D-QSAR and docking. Int. J. Mol. Sci., 2010, 11(10), 3705-3724.
[http://dx.doi.org/10.3390/ijms11103705] [PMID: 21152296]
Lu, S.; Liu, H.C.; Chen, Y-D.; Yuan, H-L.; Sun, S-L.; Gao, Y-P.; Yang, P.; Zhang, L.; Lu, T. Combined pharmacophore modeling, docking, and 3D-QSAR studies of PLK1 inhibitors. Int. J. Mol. Sci., 2011, 12(12), 8713-8739.
[http://dx.doi.org/10.3390/ijms12128713] [PMID: 22272100]
He, L.; Zhou, L.; Wang, T.; Li, Z.; Tang, X. Identification of potent virtual leads to design novel Plk-1 inhibitors: Pharmacophore modelling, virtual screening and molecular docking studies. Mol. Simul., 2013, 8, 640-652.
Joshi, A.J.; Bhojwani, H.R.; Joshi, U.J. Strategies to select the best pharmacophore model: A case study in pyrazoloquinazoline class of Plk-1 inhibitors. Med. Chem. Res., 2018, 27(1), 234-260.
Bhongade, B.A.; Gadad, A.K. 3D-QSAR CoMFA/CoMSIA studies on Urokinase plasminogen activator (uPA) inhibitors: A strategic design in novel anticancer agents. Bioorg. Med. Chem., 2004, 12(10), 2797-2805.
[http://dx.doi.org/10.1016/j.bmc.2004.02.019] [PMID: 15110861]
Bhongade, B.A.; Gadad, A.K. Insight into the structural requirements of urokinase plasminogen activator (uPA) inhibitors based on 3D-QSAR models. J. Med. Chem., 2006, 49(2), 475-489.
[http://dx.doi.org/10.1021/jm050149r] [PMID: 16420035]
Bhongade, B.A.; Amnerkar, N.D.; Talath, S.; Bhusari, K.P.; Gadad, A.K. 3D-QSAR studies on isocoumarine-based urokinase-type plasminogen activator (uPA) inhibitors employing linear and non-linear regression analysis methods. Lett. Drug Des. Discov., 2012, 9, 874-880.
VLifeMDS 3.5. Molecular design suite. VLife Sciences Technologies Pvt. Ltd., 2007.
Halgren, T.A. Merck molecular force field. II. MMFF94 Van der Waals and electrostatic parameters for intermolecular interactions. J. Comput. Chem., 1996, 17, 520-552.
Gasteiger, J.; Marsili, M. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron, 1980, 36, 3219-3228.
Wold, S. PLS for multivariate linear modeling.Chemometric methods in molecular design; Waterbeemed, V.D., Ed.; VCH Publishers: Weinheim, Germany, 1995, pp. 195-218.
Bikadi, Z.; Hazai, E. Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. J. Cheminform., 2009, 1, 15.
[http://dx.doi.org/10.1186/1758-2946-1-15] [PMID: 20150996]
Solis, F.J.; Wets, R.J.B. Minimization by random search techniques. Math. Oper. Res., 1981, 6(1), 19-30.

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Year: 2020
Page: [388 - 395]
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DOI: 10.2174/1570180816666190611161332
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