FPFT-2216, a novel anti-lymphoma compound, induces simultaneous degradation of IKZF1/3 and CK1α to activate p53 and inhibit NF-κB signaling.

Reducing casein kinase 1α (CK1α) expression inhibits the growth of multiple cancer cell lines, making it a potential therapeutic target for cancer. Herein, we evaluated the anti-tumor activity of FPFT-2216-a novel low molecular weight compound-in lymphoid tumors and elucidated its molecular mechanism of action. Additionally, we determined whether targeting CK1α with FPFT-2216 is useful for treating hematopoietic malignancies. FPFT-2216 strongly degraded CK1α and IKAROS family zinc finger 1/3 (IKZF1/3) via proteasomal degradation. FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2. Combining FPFT-2216 with an MDM2 inhibitor exhibited synergistic anti-proliferative activity and induced rapid tumor regression in immuno-deficient mice subcutaneously transplanted with a human lymphoma cell line. Nearly all tumors in mice disappeared after ten days; this was continuously observed in 5/7 mice up to 24 days after the final FPFT-2216 administration. FPFT-2216 also enhanced the anti-tumor activity of rituximab and showed anti-tumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model. Furthermore, FPFT-2216 decreased the activity of the CARD11/BCL10/MALT1 (CBM) complex and inhibited IκBα and NF-κB phosphorylation. These effects were mediated through CK1α degradation and were stronger than those of known IKZF1/3 degraders. In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NF-κB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma.