PI3Kδ-IN-8 is a powerful and specific oral inhibitor of PI3Kδ, exhibiting an IC50 of 3.3 nM. It demonstrates preferential inhibition of PI3Kδ when compared to PI3Kα, PI3Kβ, and PI3Kγ, with IC50 values of 377.2 nM, 241.6 nM, and 17.9 nM, respectively. Furthermore, PI3Kδ-IN-8 possesses notable anti-tumor efficacy.

PI3Kα:377.2 nM (IC50), PI3Kβ:241.6 nM (IC50), PI3Kδ:3.3 nM (IC50), PI3Kγ:17.9 nM (IC50)

PI3Kδ-IN-8 (compound 34), at concentrations from 0.1 nM to 10 μM over 96 hours, demonstrates strong efficacy against DLBCL cell lines, including GCB (SUDHL-6) and ABC subtypes (OCI-Ly10 and TMD-8)[1]. A 1-hour treatment with PI3Kδ-IN-8 effectively inhibits PI3K-induced AKT phosphorylation in anti-IgM stimulated Raji cells, achieving an IC50 of 9.5 nM[1]. In a Cell Viability Assay[1] on SUDHL-6, OCI-Ly10, and TMD-8 cell lines with concentrations ranging from 0.1 nM to 10,000 nM over 96 hours, the compound significantly reduced cell viability, with IC50 values of <0.1 nM for SUDHL-6 and TMD-8, and <1 nM for OCI-Ly10.

PI3Kδ-IN-8, at doses of 1-30 mg/kg administered orally once daily for 24 days, significantly decreases tumor volume and weight in a dose-responsive manner in female NOD scid mice injected with OCI-Ly10 cells, achieving an ED50 of 6.47 mg/kg and showing an 81.95% inhibition in tumor growth[1]. When administered intravenously at 1 mg/kg, PI3Kδ-IN-8 exhibits a suitable half-life (1 h), maximum concentration (C max) of 2.3 μM, and a low clearance rate (5.6 mL/min/kg) in male BALB/c mice. Oral administration at 10 mg/kg results in moderate bioavailability (39%), with a C max of 7.5 μM and an area under the curve (AUC last) of 22 μM⋅h[1]. These findings demonstrate PI3Kδ-IN-8’s potent antitumor activity along with its pharmacokinetic profiles including clearance, half-life, and bioavailability in mice.