GDC-0326 is a potent and selective PI3Kα inhibitor with a Ki of 0.2 nM.
GDC-0326 is highly selective over other kinases. In a panel of 235 kinases, only one is inhibited by >50% by GDC-0326 when tested at 1 uM. GDC-0326 is not an inhibitor of cytochrome P450 enzymes tested (IC50>10 uM against 3A4, 2C9 1A2, 2C19, 2D6), is highly permeable in MDCK cells and has thermodynamic solubility of 82 ug/mL at pH 7.4[1].
GDC-0326 is highly stable in human and rat liver microsomes, and there is a good correlation with in vivo rat clearance. It is found to have consistently low clearance and high oral bioavailability across species tested, enabling significant sustained free drug levels. Daily administration of GDC-0326 orally at 0.78, 1.56, 3.25, 6.25, or 12.5 mg/kg results in dose-dependent increase in TGI (73%, 79%, 83%, 101%, and 110%, respectively) and tumor regressions (6 PRs out of 10 animal at 6.25 and 12.5 mg/kg) when compared to vehicle treated mice. Daily administration of GDC-0326 orally at 0.78, 1.56, 3.25, 6.25, or 12.5 mg/kg also results in dose-dependent increase in TGI (73%, 97%, 97%, 122%, and 121%, respectively) in the KPL-4 xenograft model. Notably, maximum efficacy of GDC-0326 is observed at 6.25 mg/kg in the KPL-4 model based on TGI and tumor regressions (9 PRs and 1 CR out of 10 animal treated) when compared to vehicle treated mice. Doses of GDC-0326 up to 12.5 mg/kg are well tolerated based on less than 10% body weight loss (data not shown)[1].
References:
[1]. Heffron TP, et al. The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326). J Med Chem. 2016 Feb 11;59(3):985-1002.