The importance of the trifluoromethyl group in the polypharmacological profile of nilotinib was investigated. Molecular editing of nilotinib led to the design, synthesis and biological evaluation of analogues where the trifluoromethyl group was replaced by a proton, fluorine and a methyl group. While these analogues were less active than nilotinib toward Abl, their activity toward Kit was comparable, with the monofluorinated analogue being the most active. Docking of nilotinib and of analogues 2a-c to the binding pocket of Abl and of Kit showed that the lack of shape complementarity in Kit is compensated by the stabilizing effect from its juxtamembrane region.
[Show abstract][Hide abstract] ABSTRACT: Activating mutations in KIT have been associated with gastrointestinal stromal tumors (GISTs). And the tyrosine kinase inhibitor imatinib mesylate has revolutionized the treatment of GISTs. Unfortunately, primary or acquired resistance to imatinib does occur in GISTs and forms a major problem. Although sunitinib malate, a multi-kinase inhibitor, has shown effectiveness against imatinib-resistant GISTs, recent studies have demonstrated that some imatinib-resistant GISTs harboring secondary mutations in KIT activation loop were also resistant to sunitinib. Therefore, new drugs capable of overcoming the dual drug resistance of GISTs probably have potential clinical utility. In this study, we investigated the efficacy of flumatinib, a inhibitor of BCR-ABL/PDGFR/KIT, against 32D cells transformed by various KIT mutants and evaluated its potency to overcome the drug resistance of certain mutants. Interestingly, our in vitro study revealed that flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P). And our in vivo study consistently suggested that flumatinib had superior efficacy compared with imatinib or sunitinib against 32D cells with the secondary mutation Y823D. At last, molecular modeling of flumatinib docked to KIT kinase domain suggested a special mechanism underlying the capability of flumatinib to overcome the drug-resistance conferred by activation loop mutations. These findings suggest that flumatinib probably is a promising therapeutic agent against GISTs resistant to both imatinib and sunitinib because of secondary mutations in the activation loop. This article is protected by copyright. All rights reserved.
Cancer Science 11/2013; 105(1). DOI:10.1111/cas.12320 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Discoidin domain-containing receptors (DDRs) exhibit a unique mechanism of action among the receptor tyrosine kinases (RTKs) since their catalytic activity is induced by extracellular collagen binding. Moreover, they are essential components in the assimilation of extracellular signals and are frequently associated with cancer progression. Recently, DDRs were reported to be significantly linked to tumor progression in breast cancer by facilitating the processes of invasion, migration, and metastasis. Here, we report the successful development of a fluorescence-based, direct binding assay for the detection of type II and III DFG-out binders for DDR2. Using sequence alignments and homology modeling, we designed a DDR2 construct appropriate for fluorescent labeling with environmentally sensitive fluorophores. Successful assay development was validated by sensitive detection of a reference DFG-out binder. Subsequent downscaling of the method led to convenient application to HTS formats. Screening of a representative compound library identified high affinity DDR2 ligands validated by orthogonal activity-based assays. Due to homology of DDR1 and DDR2 kinase domains, a subset of identified compounds was further investigated with respect to DDR1 inhibition.
[Show abstract][Hide abstract] ABSTRACT: Nilotinib (Tasigna) is a tyrosine kinase inhibitor approved by the FDA to treat chronic phase chronic myeloid leukemia patients. It is also a transport substrate of the ATP binding-cassette (ABC) drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which may have an effect on the pharmacokinetics and toxicity of this drug. The goal of this study was to identify pharmacophoric features of nilotinib in order to potentially develop specific inhibitors of BCR-ABL kinase with minimal interactions with ABC drug transporters. 3D pharmacophore modeling and quantitative structure-activity relationship (QSAR) studies were carried out on a series of nilotinib analogs to identify chemical features that contribute to inhibitory activity of nilotinib against BCR-ABL kinase activity, P-gp and ABCG2. Twenty-five derivatives of nilotinib were synthesized and were then tested to measure their activity to inhibit BCR-ABL kinase and to inhibit the function of ABC drug transporters. A set of in vitro experiments including kinase activity and cell-based transport assays and photolabeling of P-gp and ABCG2 with a transport substrate, [125I]-Iodoarylazido-prazosin (IAAP), were carried out in isolated membranes to evaluate the potency of the derivatives to inhibit the function of ABC drug transporters and BCR-ABL kinase. Sixteen, fourteen and ten compounds were selected as QSAR datasets, respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL kinase, ABCG2 and P-gp inhibitors. The IC50 values of these derivatives against P-gp, ABCG2 or BCR-ABL kinase were used to generate pharmacophore features required for optimal interactions with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for ABCG2 inhibitory activity and a seven-point pharmacophore (AADDRRR) for P-gp inhibitory activity were generated. The derived models clearly demonstrate high predictive power for test sets of BCR-ABL, ABCG2 and P-gp inhibitors. In aggregate, these results should aid in the development of specific inhibitors of BCR-ABL kinase, that exhibit no or minimal interaction with ABC drug transporters.
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