PI3Kδ/γ-IN-2

PI3Kδ/γ-IN-2 is a potent PI3Kδ and PI3Kγ dual inhibitor with IC50s of 1 nM and 4.3 nM, respectively. PI3Kδ/γ-IN-2 has favorable oral bioavailability. PI3Kδ/γ-IN-2 has potential for battling B-cell malignancies[1].

Research Areas >> Cancer

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

PI3Kδ:1 nM (IC50)

PI3Kγ:4.3 nM (IC50)

PI3Kδ/γ-IN-2 (compound 26) (0-5 μM; 72 hours) exhibits remarkable anti-proliferative activity against SU-DHL-6 cell line[1]. PI3Kδ/γ-IN-2 (10-100 nM; 2 hours) down-regulates both phos-Akt (Ser473) and phos-S6K1 (Thr389), and decreases the phosphoration of Akt and S6K1 at 30 nM[1]. Cell Proliferation Assay Cell Line: SU-DHL-6[1] Concentration: 0-5 μM Incubation Time: 72 hours Result: Exhibited remarkable anti-proliferative activity against SU-DHL-6 cell line with GI50 value of 33 nM. Western Blot Analysis Cell Line: SU-DHL-6[1] Concentration: 10, 30 and 100 nM Incubation Time: 2 hours Result: Down-regulated both phos-Akt (Ser473) and phos-S6K1 (Thr389) in a dose-dependent manner, and exhibited a more significant decrease in the phosphoration of Akt and S6K1 at 30 nM.

PI3Kδ/γ-IN-2 (5 mg/kg; PO or IV; single) exhibits a high plasma exposure, an attractive oral bioavailability, and an acceptable clearance[1]. Pharmacokinetic Parameters of PI3Kδ/γ-IN-2 in male Sprague-Dawley rats[1]. IV (5 mg/kg) PO (5 mg/kg) T1/2 (h) 3.0 ± 0.3 14.3 ± 4.4 AUC0-t (h·μg/L) 5576 ± 606 4878 ± 694 VSS (L/kg) 3.9 ± 0.6 CL (L/h/kg) 0.9 ± 0.1 F (%) 87.5 ± 12.5 Animal Model: Male Sprague-Dawley rats[1] Dosage: 5 mg/kg Administration: PO or IV; single (Pharmacokinetics Analysis) Result: Exhibited a high plasma exposure (AUC0-t = 4878 ± 694 h μg/L), an attractive oral bioavailability (F% = 87.5 ± 12.5), and an acceptable clearance (CL = 0.9 ± 0.1 L/h/kg).

[1]. Tao Q, et al. Structurally novel PI3Kδ/γ dual inhibitors characterized by a seven-membered spirocyclic spacer: The SARs investigation and PK evaluation. Eur J Med Chem. 2020;191:112143.