FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling

• DOI: 10.1158/2767-9764.crc-23-0264
• Publication Date: 2024-01-24T14:12:55Z
• Authors: Daiki Kanaoka; Mitsuo Yamada; Hironori Yokoyama; Satoko Nishino; Naoshi Kunimura; Hiroshi Satoyoshi; Shota Wakabayashi; Kazunori Urabe; Takafumi Ishii; Masato Nakanishi
• Keywords: BCL10

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