Design, synthesis, and biological evaluation of novel PI3Kδ/HDAC6 dual inhibitors for the treatment of non-Hodgkin's lymphoma

PI3Kδ and HDAC6 inhibitors play important roles in the treatment of lymphoma. Herein, a novel series of purine-based PI3Kδ/HDAC6 dual inhibitors have been rationally designed and synthesized by incorporating an HDAC pharmacophore into our previously reported PI3Kδ inhibitor scaffold. Structure-activity relationship (SAR) studies led to the discovery of the lead compound 22E, which showed potent inhibitory activity towards PI3Kδ and HDAC6, with IC₅₀ values of 2.4 nM and 6.2 nM, respectively. Compound 22E showed significantly enhanced antiproliferative activities against multiple non-Hodgkin's lymphoma (NHL) cells compared with either selective PI3Kδ inhibitor or HDAC6 inhibitor, with IC₅₀ values of 34 nM and 53 nM against SU-DHL-6 and JEKO-1 cells, respectively. Subsequent mechanistic studies revealed that compound 22E effectively arrested the cell cycle in the G0/G1 phase and induced cell apoptosis in SU-DHL-6 and JEKO-1 cells. Meanwhile, 22E could simultaneously block the PI3K/AKT/mTOR signaling pathway as well as increase the acetylation of α-tubulin and histone H3 levels. In addition, 22E prevented tumor growth in both SU-DHL-6 and JEKO-1 xenograft models, and there was no observable toxicity. These results demonstrated that 22E is a promising lead candidate with novel antitumor mechanism for the treatment of NHL.