PI3Kδ-IN-10

PI3Kδ-IN-10 is a highly potent and orally active PI3Kδ inhibitor with IC50 of 2 nM. PI3Kδ-IN-10 robustly suppresses the downstream AKT pathway to induce subsequent apoptosis in hepatocellular carcinoma models[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> PI3K/Akt/mTOR >> PI3K

Signaling Pathways >> PI3K/Akt/mTOR >> Akt

PI3Kδ:2 nM (IC50)

PI3Kδ-IN-10 (compound 9x) (0-10 μM; 72 hours) has cell proliferation inhibitory effects in HCC cell lines with IC50 of 0.53 - 1.36 μM[1]. PI3Kδ-IN-10 (0-50 μM; 24 hours) markedly enhances expression level of cleaved PARP and cleaved caspase-3, also reduces the level of Akt phosphorylation at Ser473 and Thr308 in a dose-dependent manner[1]. Cell Proliferation Assay Cell Line: Bel-7402, HepG2, Hep3B[1] Concentration: 0-10 μM Incubation Time: 72 hours Result: Showed cell proliferation inhibitory effects in HCC cell lines with IC50 of 0.53 - 1.36 μM. Western Blot Analysis Cell Line: Bel-7402, HepG2[1] Concentration: 0 μM, 1.56 μM, 3.12 μM, 6.25 μM, 12.5 μM, 50 μM Incubation Time: 24 hours Result: Markedly enhanced expression level of cleaved PARP and cleaved caspase-3, also reduced the level of Akt phosphorylation at Ser473 and Thr308 in a dose-dependent manner.

PI3Kδ-IN-10 (5 mg/kg for PO, 1 mg/kg for IV, single) exhibits an acceptable half-life (T1/2), a moderate distribution volume, and acceptable oral bioavailability[1]. PI3Kδ-IN-10 (40 and 20 mg/kg; IV, for 12 days) effectively suppress the growth of live cancer xenografts with inhibition ratios of 76.02% and 59.15% at 40 mg/kg and 20 mg/kg[1]. Pharmacokinetic Parameters of PI3Kδ-IN-10 in female Balb/c (nu/nu) mice[1]. PO (5 mg/kg) IV (1 mg/kg) T1/2 (h) 2.502 1.131 AUC (h·μg/L) 3067.94 2791.37 Vz/F (L/kg) 6.15 0.587 Tmax (h) 3 0.083 F (%) 22.0 Animal Model: Female Balb/c (nu/nu) mice[1] Dosage: 5 mg/kg or 1 mg/kg Administration: PO and IV, single (Pharmacokinetic Analysis) Result: Exhibited an acceptable half-life (T1/2), a moderate distribution volume, and acceptable oral bioavailability. Animal Model: Female Balb/c (nu/nu) mice (6 weeks)[1] Dosage: 40 and 20 mg/kg Administration: IV, for 12 days Result: Effectively suppressed the growth of live cancer xenografts with inhibition ratios of 76.02% and 59.15% at 40 mg/kg and 20 mg/kg.

[1]. Qi J, Wang W, Tang Y, et al. Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma. J Med Chem. 2022;65(5):3849-3865.