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Purity: ≥98%
Onalespib (formerly also known as AT13387; AT-13387) is an orally bioavailable small-molecule Hsp90 inhibitor (IC50 = 18 nM in A375 cells) with long-lasting anti-tumor activity. AT13387 selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins.
| Targets |
Hsp90 (Kd = 0.71 nM)
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|---|---|
| ln Vitro |
Glioma cell migration, survival, and proliferation are inhibited by onalespib lactate (0-0.4 µM; 72 h, 48 h) [2]. AKT, P-AKT, ERK1/2, P-ERK1/2, S6, and P-S6 protein expression are all decreased in a dose-dependent manner by onalespib lactate (0-0.4 µM; 48 h)[2].
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| ln Vivo |
In 6-week-old ICR mice, onalespib lactate (30 mg/kg; intraperitoneal; once) passes the blood-brain barrier (BBB) and results in long-lasting inhibition of HSP90 [2]. In zebrafish embryos, onalespib lactate (0.5 µM; 5 to 10 days after transplanting) and TMZ (10 µM) inhibit tumor growth and increase survival [2]. In HCT116 and A431 xenografts, onalespib lactate (5, 10 mg/kg for HCT116 xenografts, 20 mg/kg for A431 xenografts; i.p.; once daily for 3 days) showed anticancer efficacy [3].
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| Enzyme Assay |
Isothermal Titration Calorimetry (ITC) [4]
ITC experiments were performed on a MircoCal VP-ITC at 25°C in a buffer comprising 25 mM Tris, 100 mM NaCl, 1 mM MgCl2 and 1mM TCEP at pH 7.4. The final DMSO concentration was between 1-5%. The protein used was the same Hsp90 N-terminal ATPase domain construct used in both X-ray crystallography work. The majority of ITC experiments were set up with protein in the sample cell and compound in the injection syringe although in cases where compound solubility was limiting this was reversed. Data were fit to a single site binding model using Origin 7.0 software. All the stoichiometry values from the data analysis were in the range 0.8-1.3, providing an excellent internal control for the quality, purity and stability of both the protein and the compounds. The stoichiometry parameter was fixed at 1 in cases where the Kd value was greater than the protein concentration.53 Using the procedure outlined above, ADP and 17-DMAG had measured dissociation constants of 9.2 µM and 0.21 µM. These values are in good agreement with literature dissociation constants with the full length human Hsp90 protein of 11 µM for ADP, and 0.35 µM for 17-DMAG.32 A competition format ITC was necessary to accurately determine the affinity of compound 31. 54 This required pre-incubating the protein with one of our moderately potent phenol compounds in the sample cell prior to initiating the titration with compound 31. A competition binding model was used to fit the data and obtain a Kd estimate for compound 31. |
| Cell Assay |
Cell Proliferation Assay[2]
Cell Types: LN229, U251 and A172 cells Tested Concentrations: 0.1, 0.2, 0.4 µM Incubation Duration: 72 h Experimental Results: Inhibited cell proliferation in a dose-dependent manner. Western Blot Analysis[2] Cell Types: LN229, U251 and A172 cells Tested Concentrations: 0.1, 0.2, 0.4 µM Incubation Duration: 48 h Experimental Results: diminished the expression of EGFR, p-EGFR, AKT, P-AKT, ERK1/2, P-ERK1/2, S6, P- S6 protein in a dose-dependent manner. |
| Animal Protocol |
Animal/Disease Models: Female nu/nu balb/c (Bagg ALBino) mouse (HCT116 and A431 xenografts)[3]
Doses: 5, 10 mg/kg for HCT116 xenografts, 20 mg/kg for A431 xenografts Route of Administration: Ip; on day 1, 2, and 3 days Experimental Results: Inhibited tumor growth and had a median survival of 9.5 days and the maximum survival was 14 days in HCT116 xenografts, decreased the tumor size Dramatically by 32% in A431 xenografts. In vivo Efficacy Study. [4] HCT116 cells were injected SC into the right hind flank of male nude BALB/c mice. Tumours were apparent 7 to 10 days later. Mice were arranged into matched groups of 12 according to tumour volume giving a group mean of approximately 100 mm3 at initiation of dosing. Tumour volumes were measured S42 every 2 days. Statistical significance between groups was assessed using nonparametric one-way ANOVA. Mice were given the lactate salt of AT13387 (compound 35) using a repeated cycle of dosing of once per day for three days, no dose for three days, once per day for three days etc., for four dosing cycles at 60 mg/kg/dose (as free base equivalents) dissolved in 17.5% hydroxypropylβ-cyclodextrin via the IP route. Control mice received dose vehicle only via the same route. Tolerability was assessed by recording body weight, clinical observations and survival. AT13387 (compound 35) was well tolerated at the dose administered. Compound 1 and 17 (as the hydrochloride salt) were dosed qd (once daily) by the IP route and compound 18 (as the hydrochloride salt) was dosed q2d (every other day) by the same route, using the doses indicated below. An initial dose ranging tolerability study was performed prior to all in vivo efficacy experiments to select the most appropriate dose range. For all of the efficacy experiments carried out during the screening phase, the maximum doses used ranged between 40 and 80 mg/kg. [4] Pharmacokinetic Study Methods. [4] Plasma pharmacokinetic parameters of compounds 1, 17, 18 and 35 were determined after IV administration of individual compounds to BALB/c mice. Dosing details are given in Table A. AT13387 (compound 35) was also dosed by the oral route, formulated in 30% sterile water; 70% HPβCD (25% w/v aq) at a dose level of 50 mg free base equivalent/kg. |
| References |
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| Additional Infomation |
Onalespib Lactate is the lactate form of onalespib, a synthetic, orally bioavailable, small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Onalespib selectively binds to Hsp90, thereby inhibiting its chaperone function and promoting the degradation of oncogenic signaling proteins involved in tumor cell proliferation and survival. Hsp90, a chaperone protein upregulated in a variety of tumor cells, regulates the folding, stability and degradation of many oncogenic signaling proteins.
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| Molecular Formula |
C27H37N3O6
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|---|---|
| Molecular Weight |
499.599187612534
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| Exact Mass |
499.268
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| Elemental Analysis |
C, 64.91; H, 7.47; N, 8.41; O, 19.21
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| CAS # |
1019889-35-0
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| Related CAS # |
Onalespib;912999-49-6
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| PubChem CID |
46915024
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
36
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| Complexity |
651
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(C1C(=CC(=C(C(C)C)C=1)O)O)N1CC2C=CC(=CC=2C1)CN1CCN(C)CC1.O[C@H](C(=O)O)C
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| InChi Key |
VYRWEWHOAMGLLW-WNQIDUERSA-N
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| InChi Code |
InChI=1S/C24H31N3O3.C3H6O3/c1-16(2)20-11-21(23(29)12-22(20)28)24(30)27-14-18-5-4-17(10-19(18)15-27)13-26-8-6-25(3)7-9-26;1-2(4)3(5)6/h4-5,10-12,16,28-29H,6-9,13-15H2,1-3H3;2,4H,1H3,(H,5,6)/t;2-/m.0/s1
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| Chemical Name |
(2,4-dihydroxy-5-isopropylphenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone (S)-2-hydroxypropanoate
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| Synonyms |
Onalespib lactate; AT-13387 lactate; ATI 13387; AT-13387 lactate; 1019889-35-0; Onalespib lactate [USAN]; ATI-13387AU; ATI-13387A; Onalespib l-lactate; UNII-66226JUH2I; ATI-13387A; ATI-13387; ATI-13387AU; ATI13387.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0016 mL | 10.0080 mL | 20.0160 mL | |
| 5 mM | 0.4003 mL | 2.0016 mL | 4.0032 mL | |
| 10 mM | 0.2002 mL | 1.0008 mL | 2.0016 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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