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[2].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.
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. 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).