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Pimitespib

MCE China：Pimitespib

Brand：MedChemExpress (MCE)

Cat. No.HY-15785

CAS：1260533-36-5

Synonyms：TAS-116

Purity：98.79%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 1 year -20°C 6 months

Shipping：Room temperature in continental US; may vary elsewhere.

Description：Pimitespib (TAS-116) is an oral bioavailable, ATP-competitive, highly specific HSP90α/HSP90β inhibitor (Kis of 34.7 nM and 21.3 nM, respectively) without inhibiting other HSP90 family proteins such as GRP94. Pimitespib demonstrates less ocular toxicity.

In Vitro：Pimitespib 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 Pimitespib highly specific for Hsp-90α/β without inhibiting other Hsp-90 family proteins such as GRP94 in endoplasmic reticulum or TRAP-1 in mitochondria[3]. Pimitespib (0-5 μM, 48 hours) inhibits human retinal pigment epithelial ARPE-19 cell lines and NCI-H929 MM cells growth[2]. More significant degradation of p-C-Raf and p-MEK1/2, HSP90 client proteins and key RAS/RAF/MEK pathway regulators, is triggered by Pimitespib (0.125-1 μM, 24 hours) than 17-AAG in INA6 and NCI-H929 MM cells[2].

In Vivo：Pimitespib (12.0 mg/kg, p.o., 14 days) shows antitumor activity without inducing eye injury in rats. Pimitespib is distributed less in retina than in plasma in rats; consequently, Pimitespib does not produce any detectable photoreceptor injury[1]. Pimitespib triggers enhanced in vivo anti-MM activities, both alone and in combination with PS-341 (BTZ), with a favorable safety profile. Mice treated with Pimitespib (10 mg/kg and 15 mg/kg, orally, 38 days), BTZ, or Pimitespib plus BTZ show significantly enhance growth inhibition versus the vehicle control group. Median overall survival of treated animals (Pimitespib, 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[2]. The favorable pharmacokinetic profile of Pimitespib is reflected in its dose-dependent antitumor activity; the T/C (tumor volume of Pimitespib-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. Pimitespib is orally absorbed and has a bioavailability of almost 100% in mice, and 69.0% in rats. Pimitespib 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.)). Pimitespib is more rapidly eliminated from retina (t1/2=3.4 hours) than the other HSP90 inhibitors (t1/2=7.1-19.1 hours)[1].

IC50 & Target：HSP90α 34.7 nM (Ki) HSP90β 21.3 nM (Ki)

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References：

[1]. Ohkubo S, et al. 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.  [Content Brief]

[2]. Suzuki R, et al. Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with PS-341 in multiple myeloma. Leukemia. 2015 Feb;29(2):510-4.  [Content Brief]

[3]. Utsugi T. New challenges and inspired answers for anticancer drug discovery and development. Jpn J Clin Oncol. 2013 Oct;43(10):945-53.  [Content Brief]