FMS-like tyrosine kinase 3 (FLT3) inhibitors: Molecular docking and experimental studies.

Autor: Mashkani B; Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia. Electronic address: Baratali.Mashkani@uon.edu.au., Tanipour MH; Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: TanipourMH2@mums.ac.ir., Saadatmandzadeh M; Department of Chemistry, Faculty of Sciences, Ferdowsi University, Mashhad, Iran., Ashman LK; School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia. Electronic address: leonie.ashman@newcastle.edu.au., Griffith R; School of Medical Sciences/Pharmacology, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: r.griffith@unsw.edu.au.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2016 Apr 05; Vol. 776, pp. 156-66. Date of Electronic Publication: 2016 Feb 16.
DOI: 10.1016/j.ejphar.2016.02.048
Abstrakt: Activating mutations in FMS-like tyrosine kinase 3 (FLT3) occur in 25% of acute lymphoid and 30% of acute myeloid leukaemia cases. Therefore, FLT3 is a potential therapeutic target for small molecule kinase inhibitors. In this study, protein-ligand interactions between FLT3 and kinase inhibitors (CEP701, PKC412, sunitinib, imatinib and dasatinib) were obtained through homology modelling and molecular docking. A cellular system for experimental testing of the inhibitors was also established by expressing wildtype and internal tandem duplication mutant FLT3 (FLT3-WT and FLT3-ITD) in FDC-P1 cells. Imatinib and dasatinib could not be docked into any of the FLT3 models, consistent with their lack of activity in the experimental assays. CEP701, PKC412 and sunitinib interacted with the ATP-binding pocket of FLT3, forming H-bonds with Cys694 and Glu692. Based on the EC50 values in the cell proliferation assay, CEP701 was the most potent inhibitor; sunitinib and PKC412 were ranked second and third, respectively. Sunitinib was the most selective inhibitor, followed by PKC421 and CEP701. The potency of sunitinib and to a lesser extent CEP701 in inhibition of FLT3 autophosphorylation was lower than the cell proliferation inhibition, indicating that inhibition of FLT3 downstream proteins may contribute to the cellular effects. It was shown in this study that the docking procedure was able to differentiate FLT3 inhibitors from ineffective compounds. Additionally, interaction with the phosphate binding region in the ATP-binding pocket increased potency at the cost of selectivity. These findings can be applied in designing highly effective and selective inhibitors for FLT3 and other related kinases.
(Copyright © 2016 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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