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FIGURE 5 from FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling

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posted on 2024-02-06, 14:20 authored by Daiki Kanaoka, Mitsuo Yamada, Hironori Yokoyama, Satoko Nishino, Naoshi Kunimura, Hiroshi Satoyoshi, Shota Wakabayashi, Kazunori Urabe, Takafumi Ishii, Masato Nakanishi

Antitumor activity of FPFT-2216 in CDX and PDX models. FPFT-2216 (10 mg/kg) and siremadlin (100 mg/kg) were administered alone or in combination to mice subcutaneously transplanted with Z-138 cells for three weeks. Tumor volume (A) during the subsequent 3-week washout period and body weight (B) during the treatment period are shown (mean ± SEM, n = 7). **, P < 0.01; ***, P < 0.001 versus vehicle-treated group (Tukey test). C, Tumor volume when FPFT-2216 (1 mg/kg) and rituximab (30 µg/mouse) were administered alone or in combination to mice subcutaneously transplanted with Z-138 cells (mean ± SEM, n = 10). **, P < 0.01 versus vehicle-treated group (Tukey test). D, Tumor volume when FPFT-2216 (0.1 mg/kg) and rituximab (30 µg/mouse) were administered alone or in combination to mice subcutaneously transplanted with DOHH-2 cells (mean ± SEM, n = 5–6). ***, P < 0.001 versus vehicle-treated group, #P < 0.05 versus rituximab-treated group (Dunnett test). E, Cell viability (%) in non-GCB DLBCL patient-derived tumor cells treated with various concentrations of FPFT-2216 for 3 days. Results are presented as mean values (duplicate). F, Tumor volume after administering FPFT-2216 (0.1, 1 mg/kg) or cyclophosphamide (75 mg/kg) to mice subcutaneously transplanted with LYXFDLBC 2835 tumor cells derived from a patient with non-GCB DLBCL (mean ± SEM, n = 6). **, P < 0.01 versus vehicle-treated group (Dunnett test). Each figure (A, C, D, F) shows the time-dependent change in tumor volume of each group until the first individual animal was euthanized. 2216, FPFT-2216; Sire, siremadlin; RTX, rituximab; CPA, cyclophosphamide.

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ARTICLE 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 the antitumor activity of FPFT-2216—a novel low molecular weight compound—in lymphoid tumors and elucidated its molecular mechanism of action. In addition, 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 antiproliferative activity and induced rapid tumor regression in immunodeficient mice subcutaneously transplanted with a human lymphoma cell line. Nearly all tumors in mice disappeared after 10 days; this was continuously observed in 5 of 7 mice up to 24 days after the final FPFT-2216 administration. FPFT-2216 also enhanced the antitumor activity of rituximab and showed antitumor 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 NFκB 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/NFκB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma. We found potential vulnerability to CK1α degradation in certain lymphoma cells refractory to IKZF1/3 degraders. Targeting CK1α with FPFT-2216 could inhibit the growth of these cells by activating p53 signaling. Our study demonstrates the potential therapeutic application of CK1α degraders, such as FPFT-2216, for treating lymphoma.