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Purity: ≥98%
Pimitespib (TAS-116) is a novel, potent and selective inhibitor of heat shock protein 90 (Hsp90) subtypes alpha and beta [HSP90α/HSP90β] with anticancer activity. It inhibits HSP90α/HSP90β with Kis of 34.7 nM and 21.3 nM, respectively. It has potential antineoplastic and chemo/radiosensitizing activities. TAS-116 specifically binds to and inhibits the activity of Hsp90 alpha and beta; this results in the proteasomal degradation of oncogenic client proteins, which inhibits client protein dependent-signaling, induces apoptosis, and inhibits the proliferation of cells overexpressing HSP90alpha/beta.
| ln Vitro |
Pimitespib binds to both new and the traditional binding pocket of the Hsp-90 that is currently in use. Due to its distinct binding mechanism, pimitespib is extremely effective against Hsp-90α/β without attaching to other Hsp-90s. The human pigment epithelial ARPE-19 cell line and NCI-H929 MM Cell growth[2] are inhibited by pimitespib (0-5 μM, 48). Family proteins, such as GRP94 in the endoplasmic reticulum or TRAP-1 in mitochondria, are also inhibited. Pimitespib (0.125-1 μM, 24 hours) significantly degraded pC-Raf and p-MEK1/2, HSP90 client proteins and important RAS/RAF/MEK dye modulators in INA6 and NCI-H929 MM cells.
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| ln Vivo |
Pimitespib (12.0 mg/kg, lung, 14 d) does not harm the eyes and shows anticancer efficacy in malignancies. Pimitespib does not create any detectable Pimitespib-triggered boost of anti-MM activity in vivo and has a positive safety profile when administered alone or in combination with PS-341 (BTZ), as it is projected to be less dispersed than the liver. When compared to solution dye, mice treated with Pimitespib (10 mg/kg and 15 mg/kg, pass, 38 d), BTZ, or Pimitespib + BTZ demonstrated noticeably increased growth inhibition. In comparison to the solvent control, half of the dye-treated animals (Pimitespib, pass, 10 mg/kg=33 d, 15 mg/kg=37 d, BTZ=36 d, combination=56.5 d) lived noticeably longer [2]. Pimitespib's dose-dependent anticancer activity demonstrates a favorable pharmacokinetic profile; T/C (Pimitespib-treated model versus solvent-treated tumor volume of the model) was 47%, 21%, and 9%, respectively, at dosages of 3.6 mg/kg, 7.1 mg/kg, and 14.0 mg/kg. Pimitespib's bioavailability in mice following simulated absorption was nearly 100%, with a residual rate of 69.0%. In mice, the half-life of pimitespib's terminal elimination is intermediate, with t1/2=8.2 h, 2.5 h, 4.4 h, and 2.2 h for 3.6 mg/kg, face, 7.1 mg/kg, face, 14.0 mg/kg, facial, and involved (4 mg/kg, facial). Compared to other HSP90 implicates, pimitespib is removed from the trial more quickly (t1/2=3.4 hours)[1].
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| Cell Assay |
Cell viability assay [2]
Cell Types: human retinal pigment epithelial ARPE-19 cell line and NCI-H929 MM cells Tested Concentrations: 0-5 μM Incubation Duration: 48 hrs (hours) Experimental Results: Inhibits the growth of NCI-H929 MM cells with an IC50 of 0.35 μM. Western Blot Analysis[2] Cell Types: MM cell line INA6 and NCI-H929 Cell Tested Concentrations: 0.125-1 μM Incubation Duration: 24 hrs (hours) Experimental Results: Effective targeting of HSP90 client proteins, including C-Raf and MEK1/2; and inhibition of HSP27 up-regulate and overcome the 17-AAG resistance mechanism. |
| Animal Protocol |
Animal/Disease Models: Male F344 nude mice (6 weeks old) versus established NCI-H1975 xenografts (6 weeks old) [1]
Doses: 12.0 mg/kg Route of Administration: Oral; daily; two-week Experimental Results: Causes tumor shrinkage. Demonstrated anti-tumor activity in the NCI-H1975 rat xenograft model, did not cause eye damage in rats, and did not cause ocular toxicity at effective doses. Animal/Disease Models: CB17 SCID (severe combined immunodeficient) mouse (48-54 days old), mouse xenograft model [2] Doses: 10 and 15 mg/kg Route of Administration: oral; 5 days per week; continued for 28 days Experimental Results: Growth inhibition was Dramatically enhanced compared to vehicle control. The delay in tumor growth was greater in the combination treatment group compared with either treatment group alone. Animal/Disease Models: Mice, rats and dogs [1] Doses: dogs 3.0 mg/kg, rats 4.0 mg/kg, mice 3.6, 7.1 and 14.0 mg/kg Route of Administration: oral; Routine; 20-day Experimental Results: Oral absorption, without special formulation, bioavailability was nearly 100% in mice, 69.0% in rats, and 73.9% in dog |
| References |
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| Additional Infomation |
TAS-116 is under investigation in clinical trial NCT02965885 (A Study of TAS-116 in Patients With Solid Tumors).
Pimitespib is a specific inhibitor of heat shock protein 90 (Hsp90) subtypes alpha and beta, with potential antineoplastic and chemo/radiosensitizing activities. Upon oral administration, pimitespib specifically binds to and inhibits the activity of Hsp90 alpha and beta; this results in the proteasomal degradation of oncogenic client proteins, which inhibits client protein dependent-signaling, induces apoptosis, and inhibits the proliferation of cells overexpressing HSP90alpha/beta. Hsp90, a family of molecular chaperone proteins that are upregulated in a variety of tumor cells, plays a key role in the conformational maturation, stability, and function of "client" proteins within the cell,; many of which are involved in signal transduction, cell cycle regulation and apoptosis, including kinases, cell-cycle regulators, transcription factors and hormone receptors. As TAS-116 selectively inhibits cytosolic HSP90alpha and beta only and does not inhibit HSP90 paralogs, such as endoplasmic reticulum GRP94 or mitochondrial TRAP1, this agent may have less off-target toxicity as compared to non-selective HSP90 inhibitors. |
| Molecular Formula |
C25H26N8O
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|---|---|
| Molecular Weight |
454.526943683624
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| Exact Mass |
454.223
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| CAS # |
1260533-36-5
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| PubChem CID |
67501411
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| Appearance |
White to off-white solid powder
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| LogP |
4.491
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
34
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| Complexity |
721
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
JMNDKGSFCHWKBP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H26N8O/c1-5-26-25(34)17-6-8-19(9-7-17)33-24-22(23(30-33)16(2)3)21(10-11-27-24)32-14-20(28-15-32)18-12-29-31(4)13-18/h6-16H,5H2,1-4H3,(H,26,34)
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| Chemical Name |
N-ethyl-4-(3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzamide
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| Synonyms |
TAS-116 TAS 116 TAS116 Pimitespib
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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) |
DMSO : ~125 mg/mL (~275.01 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2001 mL | 11.0004 mL | 22.0007 mL | |
| 5 mM | 0.4400 mL | 2.2001 mL | 4.4001 mL | |
| 10 mM | 0.2200 mL | 1.1000 mL | 2.2001 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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