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Fig. 1 · Structure
Cat. No.
A11062
CAS No.
912999-49-6
Formula
C24H31N3O3
Mol. Weight
409.5

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Onalespib (AT13387)

Cat. No. A11062 CAS 912999-49-6

HSP90 Inhibitor

AT13387 is a targeted inhibitor of Hsp90,inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival.

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Publications for Onalespib

3 publications citing this product

  1. Boucherat O, .et al. , Am J Respir Crit Care Med, 2018, Jul 1;198(1):90-103 PMID: 29394093
  2. Olivier Boucherat, .et al. , Sci Rep, 2017, 7: 4546 PMID: 28674407
  3. Hiroki Murano, .et al. , Plant Biotechnol Rep, 2017, 11:107-113
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Biological Activity

Bioactivity / Mechanism

Onalespib (AT13387) produces cellular responses consistent with HSP90 inhibition. In GIST cells, treatment induced HSP70 and depleted the HSP90 clients KIT and AKT, with suppression of KIT-pathway phosphorylation. These experiments support a cellular mechanism without defining a biochemical binding affinity. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

Target & Activity

Target Activity Value
HSP90 (Cell-free assay) 18 nM

Cellular Effect

Cell Line Activity Value Description Reference
A549 IC50 0.05 μM Antiproliferative activity against human A549 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
A549 IC50 0.44 μM Antiproliferative activity against human A549 cells after 72 hrs by MTT assay [PMID: 30784881]
BT-474 IC50 0.032 μM Antiproliferative activity against human BT-474 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
GIST430 IC50 34 nM Cytotoxicity against imatinib-resistant human GIST430 cells assessed as decrease in cell viability after 7 days by alamar blue assay [PMID: 26844689]
GIST48 IC50 55 nM Cytotoxicity against imatinib-resistant human GIST48 cells assessed as decrease in cell viability after 7 days by alamar blue assay [PMID: 26844689]
HCT-116 IC50 0.07 μM Antiproliferative activity against human HCT-116 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
HCT-116 IC50 0.08 μM Antiproliferative activity against human HCT116 cells after 48 hrs by MTT assay [PMID: 24763261]
HCT-116 IC50 48 nM Cytotoxicity against human HCT116 cells by Alamar blue assay [PMID: 20662534]
HepG2 IC50 0.018 μM Antiproliferative activity against human HepG2 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
K562 IC50 0.038 μM Antiproliferative activity against human K562 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
L02 IC50 11.64 μM Cytotoxicity against human L02 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
MCF7 IC50 0.02 μM Antiproliferative activity against human MCF7 cells assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
MCF7 IC50 0.032 μM Antiproliferative activity against human MCF7 cells incubated for 72 hrs by MTT assay [PMID: 29028527]
MCF7 IC50 0.28 μM Antiproliferative activity against human MCF7 cells after 48 hrs by MTT assay [PMID: 24763261]
MCF7 IC50 0.29 μM Antiproliferative activity against human MCF7 cells after 72 hrs by MTT assay [PMID: 30784881]
MDA-MB-231 IC50 0.038 μM Antiproliferative activity against human MDA-MB-231 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
MDA-MB-468 IC50 0.066 μM Antiproliferative activity against human MDA-MB-468 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
MKN-28 IC50 0.129 μM Antiproliferative activity against human MKN-28 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
MV4-11 IC50 0.011 μM Antiproliferative activity against human MV4-11 assessed as reduction in cell viability incubated for 72 hrs by MTT assay [PMID: 27933959]
NCI-H1299 IC50 0.37 μM Antiproliferative activity against human NCI-H1299 cells after 72 hrs by MTT assay [PMID: 30784881]

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In Vitro Studies

In PAH pulmonary artery smooth muscle cells, AT13387 (10–100 nM, 48 hours) reduced HDAC6 protein abundance and increased acetylated α-tubulin. A concordant response to HSP90 knockdown supports HSP90-dependent regulation of HDAC6; it does not demonstrate direct inhibition of HDAC6. [2]

HSP90-dependent HDAC6 abundance in PAH smooth muscle cells

Cell-based study · Human pulmonary arterial hypertension pulmonary artery smooth muscle cells (PAH-PASMCs). [2]

AT13387 reduced HDAC6 protein abundance and increased acetylated α-tubulin. HSP90 siRNA produced a concordant response versus scrambled siRNA, supporting an HSP90-dependent cellular mechanism. This does not establish direct HDAC6 inhibition.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
HDAC6 protein abundance and acetylated α-tubulin after AT13387 exposureQualitative immunoblot response Dose-dependent reduction of HDAC6 with increased acetylated α-tubulin[2]
HDAC6 abundance following HSP90 knockdown versus scrambled siRNAMechanistic control Concordant HDAC6 reduction; siHSP90 or siSCRM, 20–100 nM for 48 hours[2]

Literature-Reported Treatment Conditions

Treatment concentration
10, 20, 50 and 100 nM AT13387
Exposure duration
48 hours
Method
Cell treatment followed by Western blotting; untreated and vehicle lanes; HSP90 knockdown versus scrambled siRNA as a mechanistic control.
Vehicle
Dimethyl sulfoxide (DMSO); final percentage not specified for AT13387 in the read methods.
Reported limits
Exact AT13387-treated donor-line count and quantitative effect sizes are not specified for panel B. Caption describes blots as representative of two independent experiments; this does not establish donor n.
Methods and source locations

Compound reported in the paper: Onalespib (AT13387); Compound label in the paper: AT13387

Applies to the reported AT13387 cellular experiment; no solid-state equivalence, clinical efficacy or direct HDAC6 inhibition inferred.

Figure 2B–C; Results: HSP90-dependent HDAC6 expression; Methods: Reagents and inhibitors, Cell culture and treatments, Quantitative RT-PCR and immunoblotting

HDAC6 protein abundance and acetylated α-tubulin after AT13387 exposure: Western blotting with α-tubulin and Amido black controls; no numerical fold change extracted — Figure 2B image/caption; corresponding Results paragraph

HDAC6 abundance following HSP90 knockdown versus scrambled siRNA: Western blotting; blots representative of two independent experiments — Figure 2C image/caption

AT13387 depletes HSP90 client proteins in GIST cells

Cell-based study · Human GIST882, GIST430 and GIST48 cells; imatinib-sensitive GIST882 and imatinib-resistant GIST430/GIST48. [1]

Concentration- and time-course immunoblots showed depletion of KIT and AKT and reduced phosphorylation of KIT-pathway proteins, with HSP70 induction. The response occurred in both imatinib-sensitive and -resistant lines.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
KIT/AKT abundance and KIT-pathway phosphorylationQualitative concentration response Client depletion and signaling inhibition across the three tested GIST lines[1]
HSP70 induction and KIT depletion during continued exposureQualitative time course Effects detectable after 6 hours and sustained through 72 hours at 250 nmol/L[1]

Literature-Reported Treatment Conditions

Treatment concentration
50, 75, 100, 150 and 250 nmol/L for the 24-hour concentration series; 250 nmol/L for the time course
Exposure duration
24 hours (concentration series); 6, 24, 48 and 72 hours (time course)
Method
Cell treatment followed by SDS-PAGE and immunoblotting; DMSO and baseline controls.
Vehicle
DMSO control shown in Figure 2; percentage for this blot experiment not specified.
Reported limits
Figure 2 does not provide a numerical replicate count or quantified effect sizes. The 0.1% DMSO condition stated for proliferation assays is not assigned to this immunoblot experiment.
Methods and source locations

Compound reported in the paper: Onalespib (AT13387); Compound label in the paper: AT13387

Reported AT13387 experiments; no salt conversion or AdooQ lot validation.

Figure 2A–B; Results: AT13387 inhibits KIT signaling; Methods: Materials, Cell culture and reagents, Western blot samples and analysis

KIT/AKT abundance and KIT-pathway phosphorylation: Western blots with actin loading control and total/protein phospho readouts — Figure 2A image/caption and corresponding Results

HSP70 induction and KIT depletion during continued exposure: Western blot time course; not a drug-washout persistence assay — Figure 2B image/caption and corresponding Results

In Vivo Studies

In GIST430 xenografts, AT13387 at 70 mg/kg intraperitoneally once weekly inhibited tumor growth versus vehicle. Combination with oral imatinib increased growth inhibition relative to either monotherapy. AT13387 monotherapy caused a reported transient mean body weight loss of 10% after the first dose. These findings are specific to this mouse model and regimen. [1]

GIST430 xenograft efficacy and tolerability

Animal study · Imatinib-resistant GIST430 human tumor xenografts in BALB/c SCID mice; Methods N = 8 per group. [1]

AT13387 slowed GIST430 xenograft growth compared with vehicle. Adding imatinib further increased growth inhibition relative to either monotherapy. Transient body weight loss occurred with AT13387, so the efficacy finding should be interpreted alongside tolerability.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Relative tumor volumeGrowth inhibition AT13387 versus vehicle: P < 0.001; combination enhanced inhibition over either monotherapy[1]
Body weight after first AT13387 doseReported mean weight loss 10%; transient, lasting no more than 6 days[1]
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
Vehicle controlVehicle-treated tumor-bearing animalsTumors increased in relative volume; comparator for the active-treatment arms.[1]
AT13387 monotherapy
70 mg/kg		Vehicle-treated tumor-bearing animalsTumor growth inhibited versus vehicle (P < 0.001, reported in Results). Mean body weight loss of 10% after the first dose was transient, lasting no more than 6 days (reported in Results).[1]
Imatinib monotherapy
50 mg/kg imatinib		Vehicle-treated tumor-bearing animalsModerate growth inhibition versus vehicle (P < 0.001); no tumor regression reported for GIST430.[1]
AT13387 plus imatinib
AT13387 70 mg/kg plus imatinib 50 mg/kg		Vehicle-treated tumor-bearing animalsGreater tumor growth inhibition than either monotherapy; no increased toxicity reported relative to monotherapy based on the reported tolerability assessments.[1]
Vehicle control
Model: GIST430 xenografts in BALB/c SCID mice; Methods N = 8 per group
Route: Intraperitoneal
Vehicle: 17.5% (w/v) hydroxypropyl-β-cyclodextrin
Reported limits: Figure 6 caption uses ambiguous wording for tumor/animal n; Methods specify N = 8 per GIST430 group. Exact tumor-volume values are not tabulated in the adopted source.
AT13387 monotherapy
Model: GIST430 xenografts in BALB/c SCID mice; Methods N = 8 per group
Route: Intraperitoneal
Frequency: Once weekly
Treatment course: 4 weeks per efficacy Methods
Vehicle: 17.5% (w/v) hydroxypropyl-β-cyclodextrin
Reported limits: Figure 6 caption uses ambiguous wording for tumor/animal n; Methods specify N = 8 per GIST430 group. Exact tumor-volume values are not tabulated in the adopted source.
Imatinib monotherapy
Model: GIST430 xenografts in BALB/c SCID mice; Methods N = 8 per group
Route: Oral
Frequency: Twice daily
Treatment course: 3 or 4 weeks stated collectively in Methods; not resolved more specifically for this arm
Vehicle: Sterile water
Reported limits: Figure 6 caption uses ambiguous wording for tumor/animal n; Methods specify N = 8 per GIST430 group. Exact tumor-volume values are not tabulated in the adopted source.
AT13387 plus imatinib
Model: GIST430 xenografts in BALB/c SCID mice; Methods N = 8 per group
Route: AT13387 intraperitoneal; imatinib oral
Frequency: AT13387 once weekly; imatinib twice daily
Treatment course: AT13387 4 weeks; imatinib 3 or 4 weeks in shared Methods
Vehicle: AT13387/control: 17.5% (w/v) hydroxypropyl-β-cyclodextrin; imatinib: sterile water
Reported limits: Figure 6 caption uses ambiguous wording for tumor/animal n; Methods specify N = 8 per GIST430 group. Exact tumor-volume values are not tabulated in the adopted source.
Methods and source locations

Compound reported in the paper: Onalespib (AT13387); Compound label in the paper: AT13387

Model-specific mouse efficacy and measured tolerability; no clinical efficacy or generalized safety claim.

Figure 6B–C and caption; Results: AT13387 significantly inhibits growth of both imatinib-sensitive and -resistant xenograft models in vivo; Methods: Xenograft efficacy studies

Relative tumor volume: Caliper measurements; ellipsoid tumor volume; relative tumor volume curves, mean ± SE. Statistical framework: one-way ANOVA with Dunnett comparison or unpaired t test; exact test for each contrast not specified. — Figure 6B–C and caption; Results: AT13387 significantly inhibits growth of both imatinib-sensitive and -resistant xenograft models in vivo; Methods: Xenograft efficacy studies

Body weight after first AT13387 dose: Body weight monitoring; 10% is from Results prose, not estimated from the curve — Figure 6C; efficacy Results paragraph on tolerability

Vehicle control · Figure 6B–C and caption; Results: AT13387 significantly inhibits growth of both imatinib-sensitive and -resistant xenograft models in vivo; Methods: Xenograft efficacy studies

AT13387 monotherapy · Figure 6B–C and caption; Results: AT13387 significantly inhibits growth of both imatinib-sensitive and -resistant xenograft models in vivo; Methods: Xenograft efficacy studies

Imatinib monotherapy · Figure 6B–C and caption; Results: AT13387 significantly inhibits growth of both imatinib-sensitive and -resistant xenograft models in vivo; Methods: Xenograft efficacy studies

AT13387 plus imatinib · Figure 6B–C and caption; Results: AT13387 significantly inhibits growth of both imatinib-sensitive and -resistant xenograft models in vivo; Methods: Xenograft efficacy studies

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 912999-49-6
Applications HSP90 Inhibitor
Formula C24H31N3O3
Molecular Weight 409.5
Synonyms AT-13387
SMILES
CC(C)C1=C(C=C(C(=C1)C(=O)N2CC3=C(C2)C=C(C=C3)CN4CCN(CC4)C)O)O

Storage & Solubility

In Vitro Solubility

Reported Solubility

SolventReported Solubility
DMSO 22 mg/mL (53.72 mM)
Water Insoluble
Ethanol Insoluble

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

In Vivo Preparation

Concentration
9 mg/mL
Vehicle
2% DMSO+30% PEG 300+ddH2O (prepare before use)

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Smyth T, Van Looy T, Curry JE, et al. The HSP90 inhibitor, AT13387, is effective against imatinib-sensitive and -resistant gastrointestinal stromal tumor models. Molecular cancer therapeutics (2012). PMID: 22714264 DOI: 10.1158/1535-7163.mct-11-1046 Source material
  2. [2] Boucherat O, Chabot S, Paulin R, et al. HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension. Scientific reports (2017). PMID: 28674407 DOI: 10.1038/s41598-017-04874-4 Source material

Publications

3 publications citing this product

  1. Boucherat O, .et al. , Am J Respir Crit Care Med, 2018, Jul 1;198(1):90-103 PMID: 29394093
  2. Olivier Boucherat, .et al. , Sci Rep, 2017, 7: 4546 PMID: 28674407
  3. Hiroki Murano, .et al. , Plant Biotechnol Rep, 2017, 11:107-113

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