Journal: PLoS ONE

Article Title: Lapatinib-Binding Protein Kinases in the African Trypanosome: Identification of Cellular Targets for Kinase-Directed Chemical Scaffolds

doi: 10.1371/journal.pone.0056150

Figure Lengend Snippet: Chemical structure of lapatinib, AEE788, and canertinib.

Article Snippet: Lapatinib, canertinib, and AEE788 were gifts from GlaxoSmithKline, Pfizer, and Novartis, respectively.

Techniques:

Journal: PLoS ONE

Article Title: Lapatinib-Binding Protein Kinases in the African Trypanosome: Identification of Cellular Targets for Kinase-Directed Chemical Scaffolds

doi: 10.1371/journal.pone.0056150

Figure Lengend Snippet: Bloodstream form T. brucei (initial cell density of 2×10 3 cells/ml) were cultured in 24-well plates for 48 h with either DMSO (control) or different concentrations of drug. Cells were counted with a hemocytometer and the graphs plotted. Data are mean ± standard deviation obtained from two independent experiments performed in duplicate. ( A ). Effect of lapatinib on growth of T. brucei . ( B ). Comparison of growth inhibitory effect of lapatinib on T. brucei to HeLa cells. HeLa and T. brucei cells were cultured for 48 h with variable concentrations of lapatinib. Relative cell density represents the live cells expressed as percentages of the control ( i.e. , DMSO-treated) experiment. ( C ) Trypanosome kill assay. Time-course of trypanocidal effect of lapatinib. Trypanosomes (10 6 cells/ml) were treated with DMSO (solvent) or lapatinib (10 µM) for 8 h: viable cells were counted every hour, and plotted for each time point.

Article Snippet: Lapatinib, canertinib, and AEE788 were gifts from GlaxoSmithKline, Pfizer, and Novartis, respectively.

Techniques: Cell Culture, Control, Standard Deviation, Comparison, Solvent

Journal: PLoS ONE

Article Title: Lapatinib-Binding Protein Kinases in the African Trypanosome: Identification of Cellular Targets for Kinase-Directed Chemical Scaffolds

doi: 10.1371/journal.pone.0056150

Figure Lengend Snippet: Proteins in total cell lysate from T. brucei were bound on ATP resin. Sepharose 4B resin was used as control. Unbound proteins (Flow through) were recovered and resin was washed sequentially with buffer A and buffer A containing 1 M KCl (Panel A). Bound proteins were eluted with lapatinib (100 µM), or AEE788 (100 µM) or canertinib (100 µM) (Panel B, C and D, respectively). Proteins were visualized by silver staining. Matrix label, A is ATP-sepharose, and S is Sepharose 4B.

Article Snippet: Lapatinib, canertinib, and AEE788 were gifts from GlaxoSmithKline, Pfizer, and Novartis, respectively.

Techniques: Control, Silver Staining

Journal: PLoS ONE

Article Title: Lapatinib-Binding Protein Kinases in the African Trypanosome: Identification of Cellular Targets for Kinase-Directed Chemical Scaffolds

doi: 10.1371/journal.pone.0056150

Figure Lengend Snippet: Proteins eluted with lapatinib, or AEE788 or canertinib after 1 M KCl and 100 µM NAD + washes of the affinity chromatography column.

Article Snippet: Lapatinib, canertinib, and AEE788 were gifts from GlaxoSmithKline, Pfizer, and Novartis, respectively.

Techniques: Affinity Chromatography

Journal: PLoS ONE

Article Title: Lapatinib-Binding Protein Kinases in the African Trypanosome: Identification of Cellular Targets for Kinase-Directed Chemical Scaffolds

doi: 10.1371/journal.pone.0056150

Figure Lengend Snippet: Closest homology templates for TbLBPK1 (magenta) and TbLBPK3 (navy) are crystallographically observed in a conformation similar to that of lapatinib-bound human EGFR (white).

Article Snippet: Lapatinib, canertinib, and AEE788 were gifts from GlaxoSmithKline, Pfizer, and Novartis, respectively.

Techniques:

Journal: PLoS ONE

Article Title: Lapatinib-Binding Protein Kinases in the African Trypanosome: Identification of Cellular Targets for Kinase-Directed Chemical Scaffolds

doi: 10.1371/journal.pone.0056150

Figure Lengend Snippet: ( A ) Alignment of lapatinib binding site residues. ( B ) Binding site structures colored according to the alignment. ( C ) Models of TbLBPK’s1-4 complexed with lapatinib.

Article Snippet: Lapatinib, canertinib, and AEE788 were gifts from GlaxoSmithKline, Pfizer, and Novartis, respectively.

Techniques: Binding Assay

Journal: PLoS ONE

Article Title: Lapatinib-Binding Protein Kinases in the African Trypanosome: Identification of Cellular Targets for Kinase-Directed Chemical Scaffolds

doi: 10.1371/journal.pone.0056150

Figure Lengend Snippet: ( A ) Predicted ICM binding scores of lapatinib (red), AEE788 (green) and canertinib (magenta) in the binding pockets of the protein kinases. The dotted line represents a hypothetical cutoff for kinase elution by drug after an NAD + wash of the affinity column. ( B ) Predicted binding poses for lapatinib (red), AEE788 (green) and canertinib (magenta) to their highest affinity protein kinases; TbLBPK1, TbLBPK2, and TbCBPK1, respectively. Kinase hinge region is shown in ribbon, ligand atom placement surface is represented by a wire mesh and colored according to its binding properties.

Article Snippet: Lapatinib, canertinib, and AEE788 were gifts from GlaxoSmithKline, Pfizer, and Novartis, respectively.

Techniques: Binding Assay, Affinity Column

Journal: Drug metabolism and drug interactions

Article Title: Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors

doi: 10.1515/dmdi-2014-0014

Figure Lengend Snippet: (A) Inhibitory potency of rifampicin toward OATP-1B1. Intracellular accumulation of OATP-1B1 substrate [3H]ES in the presence of increasing concentrations of rifampicin (0.1–100 μM). Data are shown as mean ± SD. n = 4. (B) Inhibitory potency of pazopanib toward OATP-1B1. Intracellular accumulation of OATP-1B1 substrate [3H]ES in the presence of increasing concentrations of pazopanib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (C) Inhibitory potency of nilotinib toward OATP-1B1. Intracellular accumulation of OATP-1B1 substrate [3H]ES in the presence of increasing concentrations of nilotinib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (D) Inhibitory potency of vandetanib toward OATP-1B1. Intracellular accumulation of OATP-1B1 substrate [3H]ES in the presence of increasing concentrations of vandetanib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (E) Inhibitory potency of canertinib toward OATP-1B1. Intracellular accumulation of OATP-1B1 substrate [3H]ES in the presence of increasing concentrations of canertinib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (F) Inhibitory potency of erlotinib toward OATP-1B1. Intracellular accumulation of OATP-1B1 substrate [3H]ES in the presence of increasing concentrations of erlotinib (0.1–100 μM). Data are shown as mean ± SD. n = 4.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib, nilotinib and vandetanib were purchased from LC Laboratories (Woburn, MA, UDS).

Techniques:

Journal: Drug metabolism and drug interactions

Article Title: Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors

doi: 10.1515/dmdi-2014-0014

Figure Lengend Snippet: IC 50 of tested compounds toward OATP-1B1 and -1B3 transporter proteins.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib, nilotinib and vandetanib were purchased from LC Laboratories (Woburn, MA, UDS).

Techniques:

Journal: Drug metabolism and drug interactions

Article Title: Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors

doi: 10.1515/dmdi-2014-0014

Figure Lengend Snippet: (A) Inhibitory potency of rifampicin toward OATP-1B3. Intracellular accumulation of OATP-1B3 substrate [3H]CCK-8 in the presence of increasing concentrations of rifampicin (0.1–100 μM). Data are shown as mean ± SD. n = 4. (B) Inhibitory potency of vandetanib toward OATP-1B3. Intracellular accumulation of OATP-1B3 substrate [3H]CCK-8 in the presence of increasing concentrations of vandetanib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (C) Inhibitory potency of pazopanib toward OATP-1B3. Intracellular accumulation of OATP-1B3 substrate [3H]CCK-8 in the presence of increasing concentrations of pazopanib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (D) Inhibitory potency of nilotinib toward OATP-1B3. Intracellular accumulation of OATP-1B3 substrate [3H]CCK-8 in the presence of increasing concentrations of nilotinib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (E) Inhibitory potency of canertinib toward OATP-1B3. Intracellular accumulation of OATP-1B3 substrate [3H]CCK-8 in the presence of increasing concentrations of canertinib (0.1–100 μM). Data are shown as mean ± SD. n = 4. (F) Inhibitory potency of erlotinib toward OATP-1B3. Intracellular accumulation of OATP-1B3 substrate [3H]CCK-8 in the presence of increasing concentrations of erlotinib (0.1–100 μM). Data are shown as mean ± SD. n = 4.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib, nilotinib and vandetanib were purchased from LC Laboratories (Woburn, MA, UDS).

Techniques: CCK-8 Assay

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Cellular accumulation of pazopanib (100 nM) in MDCKII cells. (A) Intracellular accumulation in WT (black bar) and MDR1 transfected cells (open bars) in the absence and presence of zosuquidar (1 μM), specific P-gp inhibitor and selected inhibitors canertinib (5 μM) and erlotinib (5 μM). (B) Cellular accumulation of pazopanib in Bcrp1 transfected cells (open bars) relative to parental WT cells (black bars) in the absence and presence of a specific Bcrp1 inhibitor Ko143 (200 nM) and canertinib (5 μM) and erlotinib (5 μM). Results are expressed as mean ± S.D., n = 4 (*p < 0.05).

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Transfection

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Transepithelial transport of pazopanib (5 μM) across MDCKII cell monolayers. Bi-directional transport was carried out in MDCKII parental, MDR1 (A) and murine Bcrp1 (B) transfected cell monolayers. Results are expressed as mean ± S.D., n = 3–4 wells.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Transfection

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Permeability values of pazopanib across MDCK-MDR1 cell monolayers.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Permeability

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Permeability values of pazopanib across MDCK-Bcrp1 cell monolayers.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Permeability

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Pazopanib brain concentration after a single intravenous dose of 5 mg/kg through tail vein in FVB-wild type mice at 60 min time point in the absence and presence of P-gp inhibitor LY335979 (zosuquidar, 25 mg/kg), Bcrp1 inhibitor Ko143 (10 mg/kg) and dual P-gp/Bcrp1 inhibitor elacridar (GF120918). Results are expressed as mean ± S.E.M., n = 3 (*p < 0.05).

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Concentration Assay

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Plasma and brain pharmacokinetic parameters obtained by noncompartmental analysis of the concentration-time profile data after an i.v. bolus dose of pazopanib in absence and presence of elacridar (GF120918) in FVB wild type mice.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Clinical Proteomics, Concentration Assay

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Influence of erlotinib and canertinib on plasma concentration profile of pazopanib after an i.v. bolus injection in FVB-wild type mice. Erlotinib and canertinib were administered intravenously 30 min prior to pazopanib through tail vein. Values are presented as mean ± S.E., n = 3.

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Clinical Proteomics, Concentration Assay, Injection

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Modulation of P-gp and Bcrp1 mediated efflux by erlotinib and canertinib: upper panels, brain concentration of pazopanib either alone or in the presence of elacridar, canertinib and erlotinib (10 mg/kg each) at t = 30 min (A) and t = 60 min (B) after an intravenous dose of 5 mg/kg pazopanib in FVB wild type mice. Lower panels, brain-plasma concentration ratio of pazopanib either alone or in the presence of elacridar, canertinib and erlotinib at t = 30 min (C) and t = 60 min (D) after an intravenous dose of 5 mg/kg in FVB wild type mice. Results are expressed as mean ± S.E., n = 3 (*p < 0.05 and **p < 0.01).

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Concentration Assay, Clinical Proteomics

Journal: International journal of pharmaceutics

Article Title: Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

doi: 10.1016/j.ijpharm.2012.05.038

Figure Lengend Snippet: Brain to plasma (Cb/Cp) concentration ratio of pazopanib at 15, 30, 60 and 120 min post dose in FVB wild type mice in the absence (vehicle treated, black bars) and presence of a P-gp and Bcrp1 dual inhibitor elacridar (gray bars). Results are expressed as mean ± S.E.M., n = 3 (*p < 0.05).

Article Snippet: Chemicals Pazopanib, erlotinib, canertinib and vandetanib were purchased from LC Laboratories (Woburn, MA).

Techniques: Clinical Proteomics, Concentration Assay