PKI-179

PKI-179 is an orally bioavailable dual inhibitor of PI3K and mammalian target of rapamycin (mTOR).¹ In an in vitro enzymatic assay, it potently inhibits PI3K (IC₅₀s = 8, 24, 17, and 74 nM for isoforms α, β, δ, and γ, respectively), two common PI3Kα mutants, E545K and H1047R (IC₅₀s = 14 and 11 nM, respectively), and mTOR (IC₅₀ = 0.42 nM). PKI-179 is selective for PI3K and mTOR over a panel of 361 other kinases at IC₅₀ values up to 50 μM, hERG (IC₅₀ > 30 μM), and cytochrome P450 (CYP) isoforms (IC₅₀s > 30 μM), but does have activity for CYP2C8 (IC₅₀ = 3 μM). It inhibits proliferation through the Akt/mTOR signaling pathway in MDA-361 breast and PC3MM2 prostate cancer cell lines in vitro (IC₅₀s = 22 and 29 nM, respectively) and inhibits tumor growth in an MDA-361 mouse xenograft model when used at a dose of 50 mg/kg.

1.Venkatesan, A.M., Chen, Z., dos Santos, O., et al.PKI-179: An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitorBioorg. Med. Chem. Lett.20(19)5869-5873(2010)