PI3Kδ-IN-10 is a highly potent and orally active PI3Kδ inhibitor (IC50 = 2 nM) that robustly suppresses the downstream AKT pathway to induce subsequent apoptosis in hepatocellular carcinoma models.

PI3Kδ:2 nM

PI3Kδ-IN-10 (compound 9x) significantly inhibits cell proliferation in HCC (Hepatocellular Carcinoma) cell lines (Bel-7402, HepG2, Hep3B) with IC50 values between 0.53 and 1.36 μM over 72 hours at concentrations up to 10 μM. At concentrations up to 50 μM for 24 hours, it also increases cleaved PARP and cleaved caspase-3 expression and decreases phosphorylation of Akt at Ser473 and Thr308 in a dose-dependent manner, indicating apoptosis induction and reduced Akt pathway activity in HCC cell lines.

PI3Kδ-IN-10 demonstrated favorable pharmacokinetics and efficacy in female Balb/c (nu/nu) mice, achieving an acceptable half-life (T 1/2), moderate distribution volume, and oral bioavailability when administered at 5 mg/kg orally (PO) and 1 mg/kg intravenously (IV). Additionally, 12-day intravenous treatments at dosages of 40 mg/kg and 20 mg/kg effectively reduced the growth of liver cancer xenografts, with inhibition ratios of 76.02% and 59.15%, respectively. This compound's pharmacokinetic parameters further illustrate its potential, showing significant area under the curve (AUC), volume of distribution adjusted by bioavailability (Vz/F), and drug absorption times (T max) across the examined dosages and methods of administration, underscoring its efficacy in the tested animal model.