Design, synthesis, and biological evaluation of 2-morpholino-4H-chromen-4-one derivatives as a potent dual PI3K/BRD4 inhibitors.

The inhibition of PI3K has only a limited therapeutic effect and often leads to drug resistance. Combining PI3K and BRD4 inhibition results in a beneficial antitumor effect in MYC-driven hematological malignancies and solid tumors, underlying the significance of developing dual kinase/epigenetic inhibitors. In this study, we report the design, synthesis, and biological evaluation of novel dual PI3K/BRD4 inhibitors. A series of benzopyranone (BP) based analogs were synthesized and subjected to structure activity relationship analysis (SAR). LCI40 displayed significant enzymatic inhibitory activity against PI3K, BRD4 proteins and demonstrated a remarkable selectivity profile against a 468 panel of kinases and 31 bromodomains. It exhibited favorable in vitro and in vivo pharmacokinetics in a mouse model. In a mantle cell lymphoma cell line (Mino), LCI40 inhibited the phosphorylation of pAKT (S473) and suppressed c-MYC levels. Further, LCI40 displayed immunomodulatory capacity with minimal toxicity to normal mouse immune cells. LCI40 is a promising lead candidate for development as a dual PI3K/BRD4 inhibitor for cancer therapy.