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

Yabing Xin,Can Xiao,Nan Wang,Huidan Wu,Wenjing Kang,Xuetao Chen,Chihong Liu,Qidong You,Zhengyu Jiang,Xiaoke Guo

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.