PIM-1/HDAC-IN-2 is a potent dual inhibitor of PIM/HDAC, exhibiting an IC50 value of 0.11 μM. It synergistically impedes cell proliferation through the inhibition of PIM1 kinase and the selective suppression of HDAC6. This compound effectively induces PARP cleavage, causing cell cycle arrest in the G1 phase and reducing S phase cells. PIM-1/HDAC-IN-2 demonstrates significant anticancer activity in the MV4-11 tumor xenograft model, with minimal toxicity.

PIM1:2.6 nM

PIM-1/HDAC-IN-2 (96 h) demonstrates cytotoxicity against various tumor cells with IC50 values of 0.11 μM (MV4-11), 3.56 μM (MOLM-13), 1.71 μM (RPMI 8226), and 7.09 μM (MM.1S). It exhibits more potent antiproliferative activity in MV4-11 cells (IC50 = 0.11 μM) compared to single-target HDACi (SAHA, IC50 = 0.53 μM) or PIM kinase inhibitor C28 (IC50 = 0.98 μM). The compound significantly enhances PARP cleavage in MV4-11 cells, showing concentration-dependent effects at 0.1-1 μM over 48 hours, and effectively induces apoptosis. Additionally, PIM-1/HDAC-IN-2 (0.1-1 μM, 48 h) causes a concentration-dependent G1 phase cell cycle arrest in MV4-11 cells while decreasing the number of S-phase cells.

PIM-1/HDAC-IN-2 (administered at doses of 50 mg/kg and 25 mg/kg via intraperitoneal injection for 21 consecutive days) demonstrated significant antitumor efficacy and tolerability in the MV4-11 tumor xenograft model.