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.
Chemical Formula: C25H26N8O
Exact Mass: 454.223
Molecular Weight: 454.538
Elemental Analysis: C, 66.06; H, 5.77; N, 24.65; O, 3.52
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)
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
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.
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).
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.
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.
Suzuki R, Kikuchi S, Harada T, Mimura N, Minami J, Ohguchi H, Yoshida Y, Sagawa M, Gorgun G, Cirstea D, Cottini F, Jakubikova J, Tai YT, Chauhan D, Richardson PG, Munshi N, Ando K, Utsugi T, Hideshima T, Anderson KC. Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells. PLoS One. 2015 Dec 2;10(12):e0143847. doi: 10.1371/journal.pone.0143847. eCollection 2015. PubMed PMID: 26630652; PubMed Central PMCID: PMC4667922.
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.
Suzuki R, Hideshima T, Mimura N, Minami J, Ohguchi H, Kikuchi S, Yoshida Y, Gorgun G, Cirstea D, Cottini F, Jakubikova J, Tai YT, Chauhan D, Richardson PG, Munshi NC, Utsugi T, Anderson KC. Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma. Leukemia. 2015 Feb;29(2):510-4. doi: 10.1038/leu.2014.300. Epub 2014 Oct 13. PubMed PMID: 25306900; PubMed Central PMCID: PMC4318711.
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