Acid−Base Profiling of Imatinib (Gleevec) and Its Fragments

Szakács, Zoltán; Béni, Szabolcs; Varga, Zoltán; Őrfi, László; Kéri, Gÿorgý; Noszál, Béla

doi:10.1021/jm049546c

Cited by 94 publications

(74 citation statements)

References 17 publications

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“…S2). Its pK a has been determined to be 7.7 by means of macroscopic pH potentiometric titrations and microscopic NMR-pH titrations (27), indicating that Gleevec can be either neutral or positively charged under physiological conditions. There is a strong indication that Gleevec is also protonated when it is bound to the kinases.…”

Section: Resultsmentioning

confidence: 99%

Explaining why Gleevec is a specific and potent inhibitor of Abl kinase

Lin

Meng

Jiang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

144

179

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Tyrosine kinases present attractive drug targets for specific types of cancers. Gleevec, a well-known therapeutic agent against chronic myelogenous leukemia, is an effective inhibitor of Abl tyrosine kinase. However, Gleevec fails to inhibit closely homologous tyrosine kinases, such as c-Src. Because many structural features of the binding site are conserved, the molecular determinants responsible for binding specificity are not immediately apparent. Some have attributed the difference in binding specificity of Gleevec to subtle variations in ligand-protein interactions (binding affinity control), whereas others have proposed that it is the conformation of the DFG motif, in which ligand binding is only accessible to Abl and not to c-Src (conformational selection control). To address this issue, the absolute binding free energy was computed using all-atom molecular dynamics simulations with explicit solvent. The results of the free energy simulations are in good agreement with experiments, thereby enabling a meaningful decomposition of the binding free energy to elucidate the factors controlling Gleevec's binding specificity. The latter is shown to be controlled by a conformational selection mechanism and also by differences in key van der Waals interactions responsible for the stabilization of Gleevec in the binding pocket of Abl.thermodynamics | alchemical free energy perturbation | sampling

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Section: Resultsmentioning

confidence: 99%

Explaining why Gleevec is a specific and potent inhibitor of Abl kinase

Lin

Meng

Jiang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

144

179

View full text Add to dashboard Cite

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“…In the human intestine, OATP1A2 is expressed on the apical brush-border membrane of human enterocytes along the entire crypt-villus axis, where it is colocalized with ABCB1 (41). Because under the mild acidic conditions in the duodenum imatinib is predicted to be >90% in a cationic form (45), it is tempting to speculate that OATP1A2 is an important transporter that facilitates the intestinal absorption of imatinib (Fig. 7).…”

Section: Discussionmentioning

confidence: 99%

Interaction of Imatinib with Human Organic Ion Carriers

Franke

Filipski

et al. 2008

Clinical Cancer Research

205

176

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Purpose: The activity of imatinib in leukemia has recently been linked with expression of the organic cation transporter 1 (OCT1) gene SLC22A1. Here, we characterized the contribution of solute carriers to imatinib transport in an effort to further understand mechanisms involved in the intracellular uptake and retention (IUR) of the drug. Experimental Design: IUR of [ 3 H]imatinib was studied in Xenopus laevis oocytes and HEK293 cells expressing OATP1A2, OATP1B1, OATP1B3, OCT1-3, OCTN1-2, or OAT1-3. Gene expression was determined in nine leukemia cell lines using the Affymetrix U133 array. Results: Imatinib was not found to be a substrate for OCT1 in oocytes (P = 0.21), whereas in HEK293 cells IUR was increased by only 1.20-fold relative to control cells (P = 0.002). Furthermore, in 74 cancer patients, the oral clearance of imatinib was not significantly altered in individuals carrying reduced-function variants in SLC22A1 (P = 0.99). Microarray analysis indicated that SLC22A1 was interrelated with gene expression of various transporters, including ABCB1, ABCC4, ABCG2 (negative), and OATP1A2 (positive). Imatinib was confirmed to be a substrate for the three efflux transporters (P < 0.05) as well as for OATP1A2 (P = 0.0001).Conclusions:This study suggests that SLC22A1 expression is a composite surrogate for expression of various transporters relevant to imatinib IUR. This observation provides a mechanistic explanation for previous studies that have linked SLC22A1 with the antitumor activity of imatinib. Because of its high expression in the intestine, ciliary body, gliomas, and leukemia cells, OATP1A2 may play a key role in imatinib pharmacokinetics-pharmacodynamics.

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“…Thus, this methodology has become the chief approach of microspeciation as reviewed recently [34]. The acid/base profiling of imatinib [66] and cetirizine [33], measured by NMR/pH titration was reported.…”

Section: Other Methodsmentioning

confidence: 99%

Physicochemical Profiling in Drug Research and Development

Takács‐Novák¹

2012

Physico-Chemical Methods in Drug Discovery and Development

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Acid−Base Profiling of Imatinib (Gleevec) and Its Fragments

Cited by 94 publications

References 17 publications

Explaining why Gleevec is a specific and potent inhibitor of Abl kinase

Explaining why Gleevec is a specific and potent inhibitor of Abl kinase

Interaction of Imatinib with Human Organic Ion Carriers

Physicochemical Profiling in Drug Research and Development

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