Pharmacophore Modeling of Nilotinib as an Inhibitor of ATP-Binding Cassette Drug Transporters and BCR-ABL Kinase Using a Three-Dimensional Quantitative Structure–Activity Relationship Approach

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. Three-dimensional pharmacophore modeling and quantitative structure–activity relationship (QSAR) studies were carried out on a series of nilotinib analogues 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 data sets, 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.

Alectinib (CH5424802) antagonizes ABCB1- and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo

“…9, 10 ABCG2 has been reported to mediate MDR to a wide variety of anticancer drugs, including mitoxantrone, topotecan, irinotecan, doxorubicin, nilotinib and imatinib. 9, 11, 12, 13 Over the past decades, numerous studies have been devoted to developing ABC transporter inhibitors. 14, 15 However, none of these inhibitors has been successful in clinical practice due to poor efficacy and unpredictable adverse effects in patients.…”

Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications

“…A main approach to abolish MDR is to discover specific inhibitors of the drug-efflux pump. For this purpose, quantitative structure-activity relationship (QSAR) analysis among the series of compounds can serve for the design of lead inhibitors ( Nicolle et al, 2009 ; Ishikawa et al, 2012 ; Marighetti et al, 2013 ; Shukla et al, 2014 ). With ABCG2, since three-dimensional structures of this protein determined by cryo-electron microscopy (EM) were very recently presented ( Taylor et al, 2017 ; Jackson et al, 2018 ), a deeper understanding of the chemicals–ABCG2 interactions will be achieved as described below.…”

Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design

“…Identifying a drug or diet-derived/natural product that can be used as a selective BCRP inhibitor in a clinical DDI study is challenging, as currently available compounds are not selective for BCRP and inhibit other transporters and drug-metabolizing enzymes (Leggas et al, 2006;Lainey et al, 2012;Fujita et al, 2013;Jamei et al, 2014;Poirier et al, 2014;Shukla et al, 2014). Upon careful consideration of inhibition data generated from various in vitro and in vivo studies, there is a high likelihood that any known BCRP inhibitor will inhibit other membrane transporters or metabolic enzymes.…”