Targeting PIM Kinases with SEL24-B489: A Promising Therapeutic Approach for Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a disease where current treatments fail in a significant number of patients, highlighting an urgent need for more effective therapies. PIM kinases have emerged as potential targets, as their genetic or pharmacological inhibition has been shown to induce apoptosis in DLBCL cell lines. To explore the impact of PIM inhibition, a new pan-PIM inhibitor, SEL24-B489, was utilized in a range of DLBCL cell lines and an in vivo xenograft model.

SEL24-B489 demonstrated toxicity to DLBCL cell lines at low-micromolar or sub-micromolar concentrations. The drug's mechanism of action involves the inhibition of protein translation, as indicated by a rapid decrease in the phosphorylation of 4EBP1 and S6 across all tested cell lines. Additionally, SEL24-B489 led to the downregulation of Myc protein in germinal center B-cell-like (GCB) DLBCL cell lines and a reduction in global RNA levels, which was linked to the inhibition of PIM-dependent histone H3 serine 10 phosphorylation and decreased phosphorylation of RNA polymerase II.

The drug also significantly downregulated multiple NFκB target genes in certain DLBCL cell lines, suggesting an impact on NFκB activity. The combination of SEL24-B489 with the BTK inhibitor ibrutinib showed synergistic growth inhibitory effects in activated B-cell-like (ABC) DLBCL cell lines. In vivo studies in a murine xenograft model using U2932 cells revealed that SEL24-B489 treatment resulted in a marked inhibition of tumor growth.

In summary, SEL24-B489, a novel pan-PIM inhibitor, has shown the ability to induce apoptosis in DLBCL cell lines at low concentrations and has demonstrated efficacy in a xenograft model. The drug's mechanisms of toxicity include the inhibition of protein translation, Myc degradation, reduction in RNA transcription, and suppression of NFκB activity. Furthermore, a synergistic effect was observed when combining SEL24-B489 with ibrutinib, providing a rationale for targeting PIM activity in DLBCL.