Design of New Therapeutic Agents Targeting FLT3 Receptor Tyrosine Kinase Using Molecular Docking and 3D-QSAR Approach

Author(s): Swapnil Pandurang Bhujbal, Seketoulie Keretsu, Seung Joo Cho*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 5 , 2020

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Graphical Abstract:


Background: FMS-like tyrosine kinase-3 (FLT3) belongs to the class III Receptor Tyrosine Kinase (RTK) family. FLT3 is involved in normal hematopoiesis and is generally expressed in early hematopoietic progenitor cells. Mutations either with an internal tandem duplication of FMS-like tyrosine kinase-3 (FLT3-ITD) or point mutation at the activation loop leads to the Acute Myeloid Leukemia (AML), a highly heterogeneous disease. Thus, FLT3 is an important therapeutic target for AML.

Methods: In the present work, docking and 3D-QSAR techniques were performed on a series of diaminopyrimidine derivatives as FLT3 kinase antagonists.

Results: Docking study recognized important active site residues such as Leu616, Gly617, Val624, Ala642, Phe830, Tyr693, Cys694, Cys695, Tyr696 and Gly697 that participate in the inhibition of FLT3 kinase. Receptor-based CoMFA, RF-CoMFA and CoMSIA models were developed. RFCoMFA model revealed relatively better statistical results compared to other models. Furthermore, the selected RF-CoMFA model was evaluated using various validation techniques. Contour maps of the RF-CoMFA illustrated that steric and electronegative substitutions were favored at R1 position whereas steric and electropositive substitutions were favored at R2 position to enhance the potency.

Conclusion: Based on the designed strategy, we derived from the contour map analysis, 14 novel FLT3 inhibitors were designed and their activities were predicted. These designed inhibitors exhibited more potent activity than the most active compounds of the dataset.

Keywords: FLT3, AML, docking, 3D-QSAR, FLT3 kinase antagonists, therapeutic agents.

Zorn, J.A.; Wang, Q.; Fujimura, E.; Barros, T.; Kuriyan, J. Crystal structure of the FLT3 kinase domain bound to the inhibitor Quizartinib (AC220). PLoS One, 2015, 10(4)e0121177
[] [PMID: 25837374]
Jarusiewicz, J.A.; Jeon, J.Y.; Connelly, M.C.; Chen, Y.; Yang, L.; Baker, S.D.; Guy, R.K. Discovery of a diaminopyrimidine FLT3 Inhibitor active against acute myeloid leukemia. ACS Omega, 2017, 2(5), 1985-2009.
[] [PMID: 28580438]
Saif, A.; Kazmi, S.F.A.; Naseem, R.; Shah, H.; Butt, M.O. Acute myeloid leukemia: Is that all there is? Cureus, 2018, 10(8)e3198
[] [PMID: 30410824]
Levis, M.; Small, D. FLT3 tyrosine kinase inhibitors. Int. J. Hematol., 2005, 82(2), 100-107.
[] [PMID: 16146839]
Sudhindra, A.; Smith, C.C. FLT3 inhibitors in AML: are we there yet? Curr. Hematol. Malig. Rep., 2014, 9(2), 174-185.
[] [PMID: 24682858]
Smith, C.C.; Zhang, C.; Lin, K.C.; Lasater, E.A.; Zhang, Y.; Massi, E.; Damon, L.E.; Pendleton, M.; Bashir, A.; Sebra, R.; Perl, A.; Kasarskis, A.; Shellooe, R.; Tsang, G.; Carias, H.; Powell, B.; Burton, E.A.; Matusow, B.; Zhang, J.; Spevak, W.; Ibrahim, P.N.; Le, M.H.; Hsu, H.H.; Habets, G.; West, B.L.; Bollag, G.; Shah, N.P. Characterizing and overriding the structural mechanism of the quizartinib-resistant FLT3” gatekeeper” F691L mutation with PLX3397. Cancer Discov., 2015, 5(6), 668-679.
[] [PMID: 25847190]
Showel, M.M.; Levis, M. Advances in treating acute myeloid leukemia. F1000Prime Rep., 2014, 6, 96.
[] [PMID: 25374674]
Takahashi, S. Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. J. Hematol. Oncol., 2011, 4(1), 13.
[] [PMID: 21453545]
Meyers, J.; Yu, Y.; Kaye, J.A.; Davis, K.L. Medicare fee-for-service enrollees with primary acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource utilization and costs. Appl. Health Econ. Health Policy, 2013, 11(3), 275-286.
[] [PMID: 23677706]
Zhi, Y.; Li, B.; Yao, C.; Li, H.; Chen, P.; Bao, J.; Qin, T.; Wang, Y.; Lu, T.; Lu, S. Discovery of the selective and efficacious inhibitors of FLT3 mutations. Eur. J. Med. Chem., 2018, 155, 303-315.
[] [PMID: 29894944]
Sutamtewagul, G.; Vigil, C.E. Clinical use of FLT3 inhibitors in acute myeloid leukemia. OncoTargets Ther., 2018, 11, 7041-7052.
[] [PMID: 30410361]
Berenstein, R. Class III receptor tyrosine kinases in acute leukemia - biological functions and modern laboratory analysis. Biomark. Insights, 2015, 10(10)(Suppl. 3), 1-14.
[] [PMID: 26309392]
Dosil, M.; Wang, S.; Lemischka, I.R. Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Mol. Cell. Biol., 1993, 13(10), 6572-6585.
[] [PMID: 7692230]
Mizuki, M.; Fenski, R.; Halfter, H.; Matsumura, I.; Schmidt, R.; Müller, C.; Grüning, W.; Kratz-Albers, K.; Serve, S.; Steur, C.; Büchner, T.; Kienast, J.; Kanakura, Y.; Berdel, W.E.; Serve, H. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood, 2000, 96(12), 3907-3914.
[] [PMID: 11090077]
Schlessinger, J. Receptor tyrosine kinases: legacy of the first two decades. Cold Spring Harb. Perspect. Biol., 2014, 6(3)a008912
[] [PMID: 24591517]
Smith, B.D.; Levis, M.; Beran, M.; Giles, F.; Kantarjian, H.; Berg, K.; Murphy, K.M.; Dauses, T.; Allebach, J.; Small, D. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood, 2004, 103(10), 3669-3676.
[] [PMID: 14726387]
Stone, R.M.; DeAngelo, D.J.; Klimek, V.; Galinsky, I.; Estey, E.; Nimer, S.D.; Grandin, W.; Lebwohl, D.; Wang, Y.; Cohen, P.; Fox, E.A.; Neuberg, D.; Clark, J.; Gilliland, D.G.; Griffin, J.D. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood, 2005, 105(1), 54-60.
[] [PMID: 15345597]
De Angelo, D.J.; Stone, R.M.; Heaney, M.L.; Nimer, S.D.; Paquette, R.; Bruner-Klisovic, R.; Caligiuri, M.A.; Cooper, M.R.; LeCerf, J-M.; Iyer, G. Phase II evaluation of the tyrosine kinase inhibitor MLN518 in patients with acute myeloid leukemia (AML) bearing a FLT3 internal tandem duplication (ITD) mutation. Blood, 2004, 104(11), 1792.
Michael, M.; Vlahovic, G.; Khamly, K.; Pierce, K.J.; Guo, F.; Olszanski, A.J. Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor. Br. J. Cancer, 2010, 103(10), 1554-1561.
[] [PMID: 20959830]
Zhang, W.; Konopleva, M.; Shi, Y.X.; McQueen, T.; Harris, D.; Ling, X.; Estrov, Z.; Quintás-Cardama, A.; Small, D.; Cortes, J.; Andreeff, M. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J. Natl. Cancer Inst., 2008, 100(3), 184-198.
[] [PMID: 18230792]
O’Farrell, A-M.; Foran, J.M.; Fiedler, W.; Serve, H.; Paquette, R.L.; Cooper, M.A.; Yuen, H.A.; Louie, S.G.; Kim, H.; Nicholas, S.; Heinrich, M.C.; Berdel, W.E.; Bello, C.; Jacobs, M.; Scigalla, P.; Manning, W.C.; Kelsey, S.; Cherrington, J.M. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin. Cancer Res., 2003, 9(15), 5465-5476.
[PMID: 14654525]
Lancet, J.E. FLT3 inhibitors for acute myeloid leukemia. Clin. Adv. Hematol. Oncol., 2015, 13(9), 573-575.
[PMID: 26452187]
Smith, C.C.; Wang, Q.; Chin, C-S.; Salerno, S.; Damon, L.E.; Levis, M.J.; Perl, A.E.; Travers, K.J.; Wang, S.; Hunt, J.P.; Zarrinkar, P.P.; Schadt, E.E.; Kasarskis, A.; Kuriyan, J.; Shah, N.P. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature, 2012, 485(7397), 260-263.
[] [PMID: 22504184]
Ke, Y-Y.; Singh, V.K.; Coumar, M.S.; Hsu, Y.C.; Wang, W-C.; Song, J-S.; Chen, C-H.; Lin, W-H.; Wu, S-H.; Hsu, J.T.; Shih, C.; Hsieh, H.P. Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification. Sci. Rep., 2015, 5, 11702.
[] [PMID: 26118648]
Mashkani, B.; Tanipour, M.H.; Saadatmandzadeh, M.; Ashman, L.K.; Griffith, R. FMS-like tyrosine kinase 3 (FLT3) inhibitors: Molecular docking and experimental studies. Eur. J. Pharmacol., 2016, 776, 156-166.
[] [PMID: 26896780]
Wold, S.; Ruhe, A.; Wold, H.; Dunn, I.W.J. The collinearity problem in linear regression. The partial least squares (PLS) approach to generalized inverses. SIAM J. Sci. Comput., 1984, 5(3), 735-743.
Clark, M.; Cramer, R.D.; Van Opdenbosch, N. Validation of the general purpose Tripos 5.2 force field. J. Comput. Chem., 1989, 10(8), 982-1012.
Halgren, T.A. MMFF VI. MMFF94s option for energy minimization studies. J. Comput. Chem., 1999, 20(7), 720-729.
Huey, R.; Morris, G.M.; Olson, A.J.; Goodsell, D.S. A semiempirical free energy force field with charge-based desolvation. J. Comput. Chem., 2007, 28(6), 1145-1152.
[] [PMID: 17274016]
Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110(18), 5959-5967.
[] [PMID: 22148765]
Kamath, S.; Buolamwini, J.K. Receptor-guided alignment-based comparative 3D-QSAR studies of benzylidene malonitrile tyrphostins as EGFR and HER-2 kinase inhibitors. J. Med. Chem., 2003, 46(22), 4657-4668.
[] [PMID: 14561085]
Gadhe, C.G.; Kothandan, G.; Cho, S.J. Large variation in electrostatic contours upon addition of steric parameters and the effect of charge calculation schemes in CoMFA on mutagenicity of MX analogues. Mol. Simul., 2012, 38(11), 861-871.
Madhavan, T.; Gadhe, C.G.; Kothandan, G.; Lee, K.; Cho, S.J. Various atomic charge calculation schemes of CoMFA on HIF‐1 inhibitors of moracin analogs. Int. J. Quantum Chem., 2012, 112(4), 995-1005.
Dowlati Beirami, A.; Hajimahdi, Z.; Zarghi, A. Docking-based 3D-QSAR (CoMFA, CoMFA-RG, CoMSIA) study on hydroquinoline and thiazinan-4-one derivatives as selective COX-2 inhibitors. J. Biomol. Struct. Dyn., 2019, 37(11), 2999-3006.
[PMID: 30035675]
Klebe, G.; Abraham, U.; Mietzner, T. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J. Med. Chem., 1994, 37(24), 4130-4146.
[] [PMID: 7990113]
Chirico, N.; Gramatica, P. Real external predictivity of QSAR models. Part 2. New intercomparable thresholds for different validation criteria and the need for scatter plot inspection. J. Chem. Inf. Model., 2012, 52(8), 2044-2058.
[] [PMID: 22721530]
Eisenberg, D.; Schwarz, E.; Komaromy, M.; Wall, R. Analysis of membrane and surface protein sequences with the hydrophobic moment plot. J. Mol. Biol., 1984, 179(1), 125-142.
[] [PMID: 6502707]
Roy, K.; Chakraborty, P.; Mitra, I.; Ojha, P.K.; Kar, S.; Das, R.N. Some case studies on application of “r(m)2” metrics for judging quality of quantitative structure-activity relationship predictions: emphasis on scaling of response data. J. Comput. Chem., 2013, 34(12), 1071-1082.
[] [PMID: 23299630]
Chirico, N.; Gramatica, P. Real external predictivity of QSAR models: how to evaluate it? Comparison of different validation criteria and proposal of using the concordance correlation coefficient. J. Chem. Inf. Model., 2011, 51(9), 2320-2335.
[] [PMID: 21800825]

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Article Details

Year: 2020
Published on: 18 May, 2020
Page: [585 - 596]
Pages: 12
DOI: 10.2174/1570180816666190618104632

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