tanespimycin  (MedChemExpress)

Journal: Science Advances

Article Title: TP53 -mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition

doi: 10.1126/sciadv.aed7122

Figure Lengend Snippet: ( A ) Icicle representation of selective hit compounds of the initial single-dose HTS assay depicting peaks of highly correlating inhibitory profiles constituting compound correlation clusters (CCCs). Concentric circles depict levels of correlation as indicated on the figure (from 0 at the center to 1 at the edge). CCC HSP90i composed of the 17-AAG and 33 of its analogs is depicted by a blue peak. ( B ) Inhibition footprint (%) obtained for compounds composing the CCC HSP90i . Orange and blue lines represent data corresponding to the 17-AAG and its analogs, respectively. ( C ) Volcano plot representation of the correlation level between compounds constituting the CCCs and the ribosomal eigengene expression values obtained for tested specimens. The horizontal dashed line indicates a P value of 0.05 and vertical dashed lines indicate correlation of 0.2 and −0.2. Orange and blue dots correspond to compounds significantly correlated and inversely correlated (correlation > |0.2|, P < 0.05), respectively. Dark blue diamonds depict compounds from the CCC HSP90i composed of the 17-AAG (indicated by a larger blue diamond) and 33 of its analogs. ( D ) Ribosomal eigengene expression values according to tier 1 (“sensitive” tier) and tier 3 (“resistant” tier) sensitivity groups for 17-AAG (left) and the best analog (right), i.e., presenting the strongest difference between the two groups. Median values are indicated by black lines on each dot plot. P values resulting from the comparison between groups are indicated on the plot. ( E ) Ribosomal eigengene expression values according to tier 1 (sensitive tier, n = 114 cell lines) and tier 3 (resistant tier, n = 98) 17-AAG sensitivity groups determined using data obtained from The Genomics of Drug Sensitivity in Cancer (GDSC) database.

Article Snippet: Alvespimicin (Selleckchem), geldanamycin (MedChemExpress), and 17-AAG (MedChemExpress) were used at 1 M for U937 cells (RRID:CVCL_0007) and 500 nM for primary specimens.

Techniques: HTS Assay, Inhibition, Expressing, Comparison

Journal: Science Advances

Article Title: TP53 -mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition

doi: 10.1126/sciadv.aed7122

Figure Lengend Snippet: ( A ) Heatmap of responses to HSP90 inhibitors (17-AAG, geldanamycin, and alvespimycin). Colors represent z -scores derived from the median inhibitory concentration (IC 50 ) values (scale shown). The bottom annotation indicates specimen subgroup [-3/del(3p) or control AML]. Columns are ordered by unsupervised hierarchical clustering of IC 50 values. ( B ) Correlation between responses to 17-AAG and alvespimycin (Pearson’s r = 0.79). The dashed line indicates least-squares regression. ( C ) Average response to HSP90 inhibitors [avg(HSP90i); mean of rescaled IC 50 values from −1 to 1] according to subgroup [-3/del(3p) versus control AML], TP53 status, and ribosomal eigengene expression (tier 1, low; and tier 3, high). ( D ) Representative Western blots of RPS14, RPL14, RPL29, and α-tubulin (TUBA; loading control) in U937 cells treated for 24 hours with DMSO or HSP90 inhibitors. ( E ) Representative Western blots of RPL29 and TUBA in primary AML cells [(A) to (D): control AML; (E) to (H): -3/del(3p)] treated for 24 hours with DMSO or HSP90 inhibitors. ( F ) Correlations between RPL29 protein levels (normalized to TUBA) and IC 50 values for each HSP90 inhibitor. Pearson’s r values are indicated; dashed lines represent least-squares regression. ( G ) Ex vivo proliferation of primary -3/del(3p) (gray) and control AML (white) following exposure to DMSO, geldanamycin, or alvespimycin. Cell counts were normalized to Fresh (D0) input and expressed as fold change at days 1 and 4 (NS, not significant). ( H ) Ex vivo viability of primary -3/del(3p) (gray) and control AML (white) after treatment, normalized to Fresh (D0), assessed at days 1 and 4.

Article Snippet: Alvespimicin (Selleckchem), geldanamycin (MedChemExpress), and 17-AAG (MedChemExpress) were used at 1 M for U937 cells (RRID:CVCL_0007) and 500 nM for primary specimens.

Techniques: Derivative Assay, Concentration Assay, Control, Expressing, Western Blot, Ex Vivo

Journal: Science Advances

Article Title: TP53 -mutant AML with ribosomal gene loss exhibits impaired protein translation and sensitivity to HSP90 inhibition

doi: 10.1126/sciadv.aed7122

Figure Lengend Snippet: ( A ) Experimental design of the 17-AAG efficacy study in mice engrafted with -3/del(3p) #1 PDX cells ( n = 5 mice per group; lines indicate treatment time points; BM asp, BM aspiration). ( B ) Body weight follow-up during the 17-AAG efficacy study ( n = 5 mice, means ± SD). ( C ) Dot plot representation of the percentage of human CD45 + cells in BM aspirates performed 3 days before the treatment initiation, after 2 weeks of treatment as well as in total BM and peripheral blood (PB) at sacrifice (dots represent individual mice, means ± SD). ( D ) Representative FACS profiles of human CD45 + engrafted cells in total BM and PB at sacrifice.

Article Snippet: Alvespimicin (Selleckchem), geldanamycin (MedChemExpress), and 17-AAG (MedChemExpress) were used at 1 M for U937 cells (RRID:CVCL_0007) and 500 nM for primary specimens.

Techniques:

Journal: Acta Pharmaceutica Sinica. B

Article Title: Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease

doi: 10.1016/j.apsb.2026.02.017

Figure Lengend Snippet: Reblastatin treatment inhibits spontaneous seizures and ameliorates reactive astrogliosis. (A) Western blotting of astrocytes treated with DMSO or reblastatin (100 nmol/L) in the presence of cycloheximide (CHX, 50 μg/mL) before harvesting (left). The line graph shows the relative fold change of EAAT2 (right, n = 3, normalized to actin). (B) Western blotting analysis for Hsp90-myc after immunoprecipitation of EAAT2-FLAG. HEK293 cells were cotransfected with Hsp90-myc and EAAT2-FLAG. 6 h after transfection, the cells were treated with or without reblastatin for 42 h (right, n = 3, normalized to actin, ∗ P < 0.05, ∗∗ P < 0.01, Student's t- test). (C) Western blotting of EAAT2 protein levels in the hippocampus of epileptic mice treated with vehicle or reblastatin (left). Reblastatin or vehicle was i.p. injected three times over the course of a week. The bar graph shows the relative fold change of EAAT2 (right, normalized to actin, n = 3, ∗∗ P < 0.01, ∗∗∗ P < 0.001, one-way ANOVA with Dunnett's post hoc test). (D–E) Assessments of reblastatin's effects in a pentetrazol (PTZ)-induced acute seizure model. Reblastatin was intraperitoneal (i.p.) injected once a day for three consecutive days; subsequently, the Racine score (D, n = 15 for each group, ∗∗ P < 0.01, Mann–Whitney U test) and onset time (E, n = 15 for each group, ∗∗ P < 0.01, Student's t- test) were assessed in response to acute PTZ injections (55 mg/kg). (F) Example seizure recordings following i.p. injection of reblastatin (4 mg/kg) or vehicle every other day. (G) Statistical analysis of seizures per day of epileptic mice treated with 4 mg/kg reblastatin ( n = 19) or vehicle ( n = 16) (∗∗ P < 0.01, paired t -test). (H) Seizure frequency fold change of 4 mg/kg reblastatin or vehicle-treated epileptic mice (normalized to baseline, ∗∗∗ P < 0.001, Student's t- test). (I) Total distance traveled in the open field test by the mice treated with reblastatin ( n = 8) and vehicle ( n = 8) (∗∗ P < 0.01, Student's t- test). (J) Time traveled in the central area in the open field test by the mice treated with reblastatin ( n = 8) and vehicle ( n = 8) (∗ P < 0.05, Student's t- test). (K) Spontaneous alternations of mice treated with reblastatin ( n = 8) and vehicle ( n = 8) (∗ P < 0.05, Student's t- test). (L) Immunofluorescence of glial fibrillary acidic protein (GFAP, left) and statistical analysis of GFAP intensity (right) in the sclerotic hippocampus of epileptic mice treated with 4 mg/kg reblastatin ( n = 16) or vehicle ( n = 15) (Left scale bar = 500 μm, Right scale bar = 100 μm, ∗ P < 0.05, Student's t- test). The results are presented as mean ± SEM. ns, not significant.

Article Snippet: Cycloheximide (CHX, HY-12320), 17-AAG (HY-10211), GA (HY-15230), and memantine (HY-B0591) were purchased from MedChemExpress (Shanghai, China).

Techniques: Western Blot, Immunoprecipitation, Transfection, Injection, MANN-WHITNEY, Immunofluorescence