Paxalisib

Paxalisib (GDC-0084) is a brain penetrant inhibitor of PI3K and mTOR, with K_is of 2 nM, 46 nM, 3 nM, 10 nM and 70 nM for PI3Kα PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively^[1]. IC50 & Target:Ki: 2 nM (PI3Kα), 46 nM (PI3Kβ), 3 nM (PI3Kδ), 10 nM (PI3Kγ), 70 nM (mTOR)^[1] In Vitro: Paxalisib (GDC-0084; Compound 16) maintains inhibition of each of the Class I PI3K isoforms but with more potent inhibition of mTOR. Paxalisib is also tested in five different GBM cell lines and is found to have antiproliferative EC₅₀s ranging from 0.3 to 1.1 μM^[1]. In Vivo: After a 25 mg/kg dose of Paxalisib (GDC-0084; Compound 16) administered orally, pAKT in normal mouse brain tissue is significantly inhibited at 1 and 6 h postdose. The potent inhibition of pAKT at both time points in this study demonstrates that Paxalisib inhibits its target behind a fully intact BBB. In addition to the pharmacodynamic effect in normal brain tissue, Paxalisib is studied in a subcutaneous U87 tumor xenograft model of glioblastoma in mice. In this study, Paxalisib achieves significant and dose-dependent tumor growth inhibition. Tumor growth inhibition is first observed at a 2.2 mg/kg dose level. Higher doses led to greater tumor growth inhibition, including tumor regressions at the 17.9 mg/kg dose level. Each of these doses is well tolerated for the duration of the study^[1].