Journal: Annals of oncology : official journal of the European Society for Medical Oncology

Article Title: Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

doi: 10.1093/annonc/mdx098

Figure Lengend Snippet: Figure 2. Comparison of efficacy for Dovitinib between primary patient tumors and PDX tumors..* P< 0.05,

Article Snippet: Dovitinib (Selleck) was administered at 50 mg/kg by oral gavage mixed with 5 mM citrate buffer in deionized water.

Techniques: Comparison

Journal: Annals of oncology : official journal of the European Society for Medical Oncology

Article Title: Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

doi: 10.1093/annonc/mdx098

Figure Lengend Snippet: Figure 4. FGFR expression signature associated with in vitro and in vivo sensitivity to dovitinib. (A) Lung cancer cell lines of CLLE database were discriminated into dovitinib-sensitive, intermediate and –resistant lines according to the IC50 with k-means clustering. (B) Each module represents a set of functionally related

Article Snippet: Dovitinib (Selleck) was administered at 50 mg/kg by oral gavage mixed with 5 mM citrate buffer in deionized water.

Techniques: Expressing, In Vitro, In Vivo

Journal: Theranostics

Article Title: Jujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer's disease through activating Axl/HSP90/PPARγ pathway

doi: 10.7150/thno.26164

Figure Lengend Snippet: JuA up-regulates HSP90β in an Axl/ERK-dependent manner. BV2 cells were treated with JuA (25 μM) for indicated periods of time (A) , or treated with JuA at indicated concentrations for 0.5 h (B) . (C) BV2 cells were pretreated with 0.1% DMSO (Ctrl), JuA (25 μM) or JuA (25 μM) + SCH772984 (10 μM) for 30 min, followed by administration of Aβ42 (5 μM) for 6 h. (D) BV2 cells were pretreated with 0.1% DMSO (Ctrl), JuA (25 μM) or JuA (25 μM) with the indicated antagonist of RTKs (Dovitinib at 1 μM, Gefinitib at 2.5 μM, Sunitinib at 2.5 μM and LDC1267 at 1 μM) for 30 min, followed by administration of Aβ42 (5 μM) for 12 h. (E) BV2 cells were pretreated with 0.1% DMSO (Ctrl), JuA (25 μM) or JuA (25 μM) with the indicated antagonist of TAM receptor (LDC1267 at 1 μM, UNC2250 at 5 μM, R428 at 5 μM) for 30 min, followed by administration of Aβ42 (5 μM) for 12 h. (F) BV2 cells were transiently transfected with non-target control siRNA or siAxl for 48 h. (G) BV2 cells were transfected with siAxl for 48 h, then pretreated with JuA (25 μM) followed by administration of Aβ42 (5 μM) for 12 h. The whole-cell proteins were subjected to western blot with the antibodies indicated. All experiments were repeated three times. * p < 0.05, ** p < 0.01, *** p < 0.001.

Article Snippet: SCH772984 (HY-50846), Dovitinib (HY-50905), Gefitinib (HY-50895), Sunitinib (HY-10255A), LDC1267 (HY-12494), UNC2250 (HY-15797), R428 (HY-15150), CHIR-99021(HY-10182) were purchased from MedChem Express (Shanghai, China).

Techniques: Transfection, Control, Western Blot

Journal: PLoS ONE

Article Title: Screening of Drugs to Treat 8p11 Myeloproliferative Syndrome Using Patient-Derived Induced Pluripotent Stem Cells with Fusion Gene CEP110-FGFR1

doi: 10.1371/journal.pone.0120841

Figure Lengend Snippet: ( a ) EMS-iPS cells and control iPS cells (control 1: 201B7 and control 2: TkDA3-1) generated by expression of four factors were co-cultured with AGM-S3 cells. After 12 days, cells derived from iPS cells were collected. CD34 + cells were isolated for clonal hematopoietic culture in the presence of various concentrations of CHIR258, PKC412, ponatinib, or imatinib. Data show mean number of colonies formed ± SD. * P < 0.05 compared to cells cultured in the absence of TKIs. ( b ) EMS-iPS cells generated by expression of four factors were co-cultured with AGM-S3 cells. After 12 days, cells derived from iPS cells were collected. CD34 + cells were isolated for suspension culture in the absence or presence of various concentrations of CHIR258, PKC412, ponatinib, or imatinib. Data show the mean ± SD of the percentage of viable cells compared to the number in untreated samples, which was set at 100%. * P < 0.05 compared to cells cultured in the absence of TKIs.

Article Snippet: CHIR258 (TKI-258/Dovitinib) and ponatinib (AP24534) were purchased from Selleck Chemicals, PKC 412 was purchased from R&D Systems, and imatinib was purchased from LC Laboratories.

Techniques: Control, Generated, Expressing, Cell Culture, Derivative Assay, Isolation, Suspension

Journal: PLoS ONE

Article Title: Screening of Drugs to Treat 8p11 Myeloproliferative Syndrome Using Patient-Derived Induced Pluripotent Stem Cells with Fusion Gene CEP110-FGFR1

doi: 10.1371/journal.pone.0120841

Figure Lengend Snippet: ( a ) May-Grünwald Giemsa staining of a cytospin preparation of primary PB cells from the EMS patient (×100 magnification). ( b ) PM MNCs (more than 90% of which were blasts) from the EMS patient were cultured in suspension in the presence of CHIR258, PKC412, ponatinib, or imatinib for 7 days. Data show mean ± SD of the percentage of viable cells compared to the number in untreated samples, which was set at 100%. * P < 0.05 compared to cells cultured in the absence of TKIs (control).

Article Snippet: CHIR258 (TKI-258/Dovitinib) and ponatinib (AP24534) were purchased from Selleck Chemicals, PKC 412 was purchased from R&D Systems, and imatinib was purchased from LC Laboratories.

Techniques: Staining, Cell Culture, Suspension, Control

Journal: Nature Communications

Article Title: Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials

doi: 10.1038/s41467-017-02777-6

Figure Lengend Snippet: Screen of in silico-predicted chemical compounds active against intracellular Mtb . a Schematic overview of the in silico predictive model. BLoad = bacterial load z -score, CViab = cell viability z -score. b Chemical compound primary screen (left panel) and rescreen (middle panel) at 10 µM in the MelJuSo- Mtb infection model using Mtb constitutively expressing stable DsRed, expressed as mean z -scores ± standard deviation. Horizontal dashed lines indicate a hit cutoff at a z -score of 2 or −2. The average z -score and standard deviation of the controls (DMSO and H-89) are displayed separately. To indicate the extent of bacterial inhibition, rescreen results are expressed both as z -score and as a percentage of control value ± standard deviation in the right panel. c CFU assay of the MelJuSo (left panel) and human primary Mφ1 (middle panel) and Mφ2 (right panel) Mtb infection models treated with the validated hit compounds from b at 10 µM. Mφ1 and Mφ2 models have been described by Verreck et al. . Representative data out of three independent experiments (MelJuSo) and data from a representative donor (Mφs) out of two (Mφ1) or five (Mφ2) different healthy blood bank donors are shown. To indicate the extent of bacterial inhibition, the results are expressed as a percentage of control value ± standard deviation. Number of replicates in the MelJuSo model: AT9283 and ENMD-2076: n = 6; dovitinib, VEGFR KI I, and DAPH 2: n = 5; DMSO and H-89: n = 9. Number of replicates in the Mφ models: AT9283, ENMD-2076, dovitinib, VEGFR KI I, and DAPH 2: n = 3; DMSO and H-89: n = 5. Statistically significant difference compared to DMSO was tested using a one-way ANOVA (MelJuSo: F (6,39) = 16.35; Mφ1: F (6,18) = 10.88; Mφ2: F (6,18) = 5.23; * p value < 0.05, ** p value < 0.01, *** p value < 0.001). d CFU assay of the human primary Mφ1 and Mφ2 models infected with two different MDR- Mtb strains (Beijing family China 16319 and Dutch outbreak 2003-1128) and treated with the validated hit compounds from c at 10 µM. Data ( n = 3 technical replicates) from a representative donor out of four different healthy blood bank donors, displayed as a percentage of the DMSO control ± standard deviation are shown. Statistically significant differences compared to DMSO were tested using a one-way ANOVA (Mφ1 Beijing: F (4,10) = 11.43; Mφ2 Beijing: F (4,10) = 3.72; Mφ1 Dutch outbreak: F (4,10) = 29.09; Mφ2 Dutch outbreak: F (4,10) = 8.81; * p value < 0.05, ** p value < 0.01, *** p value < 0.001). e Six-day treatment of Mtb broth cultures with the hit compounds at 10 µM. The Mtb antibiotic rifampicin (20 μg/ml) was used as a positive control. The average bacterial density ± standard deviation of three replicates is shown, expressed as a percentage of the DMSO control. Representative results out of three individual experiments are displayed. Statistically significant difference compared to DMSO was tested using a one-way ANOVA (F (6,25) = 101.4; ** p value < 0.01, *** p value < 0.001)

Article Snippet: Dovitinib (TKI-258, CHIR-258) was from APExBIO, Houston, TX, USA.

Techniques: In Silico, Infection, Expressing, Standard Deviation, Inhibition, Control, Colony-forming Unit Assay, Positive Control

Journal: Nature Communications

Article Title: Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials

doi: 10.1038/s41467-017-02777-6

Figure Lengend Snippet: Identification of host kinases controlling intracellular Mtb survival. a STRING network of confirmed targets of dovitinib retrieved from the ChEMBL repository Compound Bioactivity section (left panel). Individual proteins are displayed as nodes. Lines represent protein–protein interactions and the thickness of the lines indicates confidence. Proteins participating in the “transmembrane receptor tyrosine kinase signaling pathway” are displayed in red. The top 10 enriched GO terms in the “Biological Function” category are displayed along with the number of genes/proteins annotated with the indicated GO terms and the false-discovery rate (FDR) of the enrichment (right panel). b Results of a siRNA screen of the human kinome in the MelJuSo- Mtb infection model using Mtb constitutively expressing destabilized DsRed, expressed as z -scores. The average z -score ± standard deviation for each siRNA pool is displayed. A hit cutoff at z = 2 or z = –2 is displayed as a dashed line. The average z -score and standard deviation of the controls (siCTRL and siAKT) are displayed separately. SiCTRL: nontargeting siRNA pool. c STRING network of the siRNA screen hits (left panel) is displayed along the top 10 enriched GO terms in the “Biological Function” category (right panel), as in a . d Participation of individual targets of dovitinib (top row) or hits from the siRNA screen (bottom row) in the “transmembrane receptor tyrosine kinase signaling pathway” are indicated by filled squares. Proteins that are both targeted by dovitinib and were a hit in the siRNA screen are shown in magenta. Dissociation constants ( K i ) retrieved from ChEMBL are shown below for the interaction between dovitinib and ABL1, BLK, and NTRK1. e STRING analysis to identify enriched KEGG pathways using the kinases from d . The top 10 enriched KEGG pathways along with the number of genes/proteins annotated with the indicated GO terms and the FDR of the enrichment are displayed (left panel). Involvement of individual proteins is overlaid on the “neurotrophin signaling pathway” KEGG pathway retrieved from the Kyoto Encyclopedia of Genes and Genomes ( http://www.genome.jp/kegg/ ). Proteins in gray are targeted by dovitinib only, blue proteins were siRNA screening hits, and proteins in red are both targeted by dovitinib and silencing of these genes affected the Mtb bacterial load

Article Snippet: Dovitinib (TKI-258, CHIR-258) was from APExBIO, Houston, TX, USA.

Techniques: Protein-Protein interactions, Infection, Expressing, Standard Deviation