PKI-179 hydrochloride

PKI-179 hydrochloride is a potent and orally available dual PI3K/mTOR inhibitor. Its IC₅₀ values against PI3K-α, PI3K-β, PI3K-γ, PI3K-δ and mTOR are 8 nM, 24 nM, 74 nM, 77 nM and 0.42 nM respectively. It also exerts inhibitory activity against E545K and H1047R mutants with IC₅₀ values of 14 nM and 11 nM, and exhibits significant antitumor effects in in vivo models.

PI3Kδ:77 nM, PI3Kβ:24 nM, PI3Kα:8 nM, mTOR:420 nM, PI3Kγ:74 nM, E545K:14 nM, H1047R:11 nM

Methods: In vitro cell proliferation assays and kinase/ion channel/metabolic enzyme screening systems were used to evaluate the antitumor activity and selectivity of PKI-179 hydrochloride.
Results: :
1.PKI-179 hydrochloride significantly inhibited tumor cell proliferation, with IC₅₀ values of 22 nM and 29 nM for MDA361 and PC3 cells, respectively.
2.At concentrations higher than 30 μM, PKI-179 hydrochloride showed no obvious inhibitory effect on 361 other kinases, hERG, and multiple cytochrome P450 (CYP) isoforms, but exhibited certain inhibitory activity against CYP2C8 with an IC₅₀ of 3 μM [1].

Methods: Nude mice bearing MDA-361 human breast cancer xenografts were treated with oral administration to evaluate the in vivo antitumor activity, target inhibition and tolerability of PKI-179 hydrochloride. The oral bioavailability and half-life of PKI-179 hydrochloride were determined in multiple animal models including nude mice, rats, monkeys and dogs.
Results: :
1.In vivo antitumor activity and tolerability: PKI-179 hydrochloride (5–50 mg/kg, oral administration once daily for 40 days) could significantly inhibit the growth of MDA-361 human breast cancer xenografts and exhibited good tolerability in nude mice.
2.In vivo target signaling inhibition: PKI-179 hydrochloride (50 mg/kg, oral administration) effectively suppressed PI3K signaling in nude mice bearing MDA-361 tumor xenografts.
3.Oral bioavailability and half-life: PKI-179 hydrochloride displayed favorable oral bioavailability (98% in nude mice, 46% in rats, 38% in monkeys, 61% in dogs) with a long half-life (>60 minutes) [1].

Ethanol: Slightly soluble

DMF: 2.00 mg/mL (3.81 mM), Sonication is recommended.

DMSO:PBS(pH 7.2) (1:3): 0.25 mg/mL (0.48 mM), Sonication is recommended.

DMSO: 16.00 mg/mL (30.48 mM), Sonication is recommended.