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 <b>C28</b> and the HDAC inhibitor <b>SAHA</b> in MV4-11 cells, we developed a series of novel dual PIM/HDAC inhibitors. Among them, compound <b>22</b> exhibited potent antiproliferative activity in MV4-11 cells, along with robust inhibitory effects against both PIM1 and HDAC6. Flow cytometry analysis showed that <b>22</b> dose-dependently induced apoptosis in MV4-11 cells. Mechanistically, treatment with <b>22</b> remarkably induced the cleavage of PARP, thereby initiating apoptosis. Furthermore, <b>22</b> 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.