PI3Kδ/HDAC6-IN-1 (Compound 22E) is an orally active dual inhibitor of PI3Kδ and HDAC6, with IC50 values of 2.4 nM and 6.2 nM, respectively. It exhibits potent antiproliferative effects against non-Hodgkin's lymphoma (NHL) cells and demonstrates antitumor activity in vivo without significant toxicity. PI3Kδ/HDAC6-IN-1 induces cell cycle arrest at the G0/G1 phase and triggers apoptosis. Additionally, it inhibits the PI3K/AKT/mTOR signaling pathway and enhances the acetylation levels of α-tubulin and histone H3.

PI3Kδ:2.4 nM

Compound 22E, known as PI3Kδ/HDAC6-IN-1, exhibits inhibitory activity against both PI3Kδ and HDAC6 with IC50 values of 2.4 nM and 6.4 nM, respectively, and demonstrates antiproliferative effects on JEKO-1 cells at concentrations ranging from 0.1 nM to 10 μM over 24-120 hours. It enhances the thermal stability of PI3Kδ and HDAC6 at concentrations of 10-30 μM and temperatures between 45-85 °C. At concentrations of 0.1-10 μM over 4 days, PI3Kδ/HDAC6-IN-1 inhibits the proliferation of NHL cells, with IC50 values of 34 nM in SU-DHL-6 cells and 53 nM in JEKO-1 cells. Additionally, at concentrations of 3-9 μM for 24 hours, it induces G0/G1 phase arrest in SU-DHL-6 and JEKO-1 cells and triggers concentration-dependent apoptosis (Annexin V positive) in these cells after 72 hours. Furthermore, PI3Kδ/HDAC6-IN-1 suppresses PI3K and HDAC-related proteins at the cellular level in SU-DHL-6 and JEKO-1 cells within 12 hours at concentrations of 3-9 μM.

PI3Kδ/HDAC6-IN-1 (Compound 22E), administered orally at a dosage of 25 mg/kg once daily for 21 days, demonstrates antitumor potential by inhibiting the PI3K pathway and HDAC-related proteins in SU-DHL-6 and JEKO-1 tumor xenograft models in NOD-SCID mice.