TAS-116

TAS-​116, also known as Pimitespib, is a potent and selective inhibitor of heat shock protein 90 (Hsp90) subtypes alpha and beta, with 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.

Product information

CAS Number: 1260533-36-5

Molecular Weight: 454.53

Formula: C25H26N8O

Synonym:

Pimitespib

TAS-116

TAS 116

TAS116

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

Smiles: CN1C=C(C=N1)C1=CN(C=N1)C1=CC=NC2=C1C(=NN2C1C=CC(=CC=1)C(=O)NCC)C(C)C

InChiKey: JMNDKGSFCHWKBP-UHFFFAOYSA-N

InChi: 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)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

TAS-116 binds not only to the conventional-binding pockets as existing Hsp-90 inhibitors, but also to a novel-binding pocket. Such a unique binding mode makes TAS-116 highly specific for Hsp-90α/β without inhibiting other Hsp-90 family proteins such as GRP94 in endoplasmic reticulum or TRAP-1 in mitochondria. TAS-116 (0-5 μM, 48 hours) inhibits human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MM cells growth. More significant degradation of p-C-Raf and p-MEK1/2, HSP90 client proteins and key RAS/RAF/MEK pathway regulators, is triggered by TAS-116 (0.125-1 μM, 24 hours) than 17-AAG in INA6 and NCI-H929 MM cells.

In Vivo:

TAS-116 (12.0 mg/kg, p.o., 14 days) shows antitumor activity without inducing eye injury in rats. TAS-116 is distributed less in retina than in plasma in rats; consequently, TAS-116 does not produce any detectable photoreceptor injury. TAS-116 triggers enhanced in vivo anti-MM activities, both alone and in combination with PS-341 (BTZ), with a favorable safety profile. Mice treated with TAS-116 (10 mg/kg and 15 mg/kg, orally, 38 days), BTZ, or TAS-116 plus BTZ show significantly enhance growth inhibition versus the vehicle control group. Median overall survival of treated animals (TAS-116, orally, 10 mg/kg=33 days, 15 mg/kg=37 days, BTZ=36 days, and the combination=56.5 days) is significantly longer than vehicle control. The favorable pharmacokinetic profile of TAS-116 is reflected in its dose-dependent antitumor activity; the T/C (tumor volume of TAS-116-treated mice vs. vehicle-treated mice) is 47%, 21%, and 9% for doses of 3.6 mg/kg, 7.1 mg/kg, and 14.0 mg/kg, respectively. TAS-116 is orally absorbed and has a bioavailability of almost 100% in mice, and 69.0% in rats. TAS-116 has moderate terminal elimination half-life (t1/2=8.2 h, 2.5 h, 4.4 h and 2.2 h for mouse (3.6 mg/kg, p.o.), mouse (7.1 mg/kg, p.o.), mouse (14.0 mg/kg, p.o.), rat (4 mg/kg, p.o.)). TAS-116 is more rapidly eliminated from retina (t1/2=3.4 hours) than the other HSP90 inhibitors (t1/2=7.1-19.1 hours).

References:

1. Lee Y, Sunada S, Hirakawa H, Fujimori A, Nickoloff JA, Okayasu R. TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation. Mol Cancer Ther. 2017 Jan;16(1):16-24. doi: 10.1158/1535-7163.MCT-16-0573. Epub 2016 Nov 9. PubMed PMID: 28062703; PubMed Central PMCID: PMC5221699.
2. Carceller V. AACR-NCI-EORTC - 27th International Symposium - Molecular Targets and Cancer Therapeutics (November 5-9, 2015 - Boston, Massachusetts, USA). Drugs Today (Barc). 2015 Nov;51(11):669-75. doi: 10.1358/dot.2015.51.11.2434189. PubMed PMID: 26744742.
3. Ohkubo S, Kodama Y, Muraoka H, Hitotsumachi H, Yoshimura C, Kitade M, Hashimoto A, Ito K, Gomori A, Takahashi K, Shibata Y, Kanoh A, Yonekura K. TAS-116, a highly selective inhibitor of heat shock protein 90α and β, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol Cancer Ther. 2015 Jan;14(1):14-22. doi: 10.1158/1535-7163.MCT-14-0219. Epub 2014 Nov 21. PubMed PMID: 25416789.

Products are for research use only. Not for human use.