Rational Design of Novel Quinazolinone-Pyrrolodihydropyrrolone Analogs as PIM/HDAC Dual-Target Inhibitors for the Treatment of Acute Myelocytic Leukemia.

Acute myeloid leukemia (AML) patients usually exhibit suboptimal responses after receiving single target drug therapy. Simultaneously targeting multiple oncogenic pathways is a promising strategy for cancer treatment. Herein, based on the synergistic antiproliferative capacity of the PIM inhibitor C28 and the HDAC inhibitor SAHA in MV4-11 cells, we developed a series of novel dual PIM/HDAC inhibitors. Among them, compound 22 exhibited potent antiproliferative activity in MV4-11 cells, along with robust inhibitory effects against both PIM1 and HDAC6. Flow cytometry analysis showed that 22 dose-dependently induced apoptosis in MV4-11 cells. Mechanistically, treatment with 22 remarkably induced the cleavage of PARP, thereby initiating apoptosis. Furthermore, 22 demonstrated significant anticancer efficacy (TGI = 81.3%; 50 mg/kg, QD) in the MV4-11 xenograft model without notable toxicity. In conclusion, our study established the therapeutic potential of dual PIM/HDAC inhibitors and provided a tool to elucidate synergistic mechanisms underlying the combined inhibition of these targets.