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<p>The modest reduction in casein kinase 1 alpha (CK1α) by lenalidomide contributes to its clinical effectiveness in treating del(5q) myelodysplastic syndrome. However, the mechanism by which CK1α impacts lymphoma survival remains inadequately defined. We developed INNO-220, a CRBN-dependent CK1α degrader, by leveraging cytokine expression profiling in T cells. Unlike lenalidomide, INNO-220 is a highly selective and potent degrader of CK1α without affecting IKZF1/3. Screening across lymphoma cell lines revealed that cells harboring wild-type p53 and exhibiting constitutive NF-κB signaling were particularly sensitive to CK1α degradation yet resistant to Bruton tyrosine kinase inhibitors. Moreover, INNO-220 suppresses NF-κB signaling and activates p53 pathway, leading to complete inhibition of lymphoma tumor growth in vivo. Mechanistically, INNO-220 disrupts the assembly and function of the CARD11/BCL10/MALT1 complex, thereby inhibiting NF-κB signaling in stimulated T cells and lymphoma cells that harbor an activating mutation in CARD11. Moreover, we observed that activation of wild-type p53 upon INNO-220 treatment was sufficient to induce potent cancer cell death even in the absence of constitutive NF-κB activity. In summary, our findings introduce a selective CK1α degrader as a novel therapeutic approach for lymphoma, providing both mechanistic insights and a potential patient selection strategy in treating lymphoma and possibly other cancers.</p>

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A highly selective and orally bioavailable casein kinase 1 alpha degrader through p53 signaling pathway targets B-cell lymphoma cells

  • 期刊论文

  • 发表日期：

    2025年5月27日

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  • Shi Feng,
  • Ran Kong,
  • Cong Wang,
  • Qingbo Hao,
  • Xiaoyu Xie,
  • Haiyang Wang,
  • Jingjing Han,
  • Yu Zhang,
  • Jan Elsner,
  • Derek Mendy,
  • Michael Haughey,
  • Paul Krenitsky,
  • Veronique Plantevin-Krenitsky,
  • Patrick Papa,
  • Frank Mercurio,
  • Weilin Xie,
  • Xiangxiang Zhou

摘要

The modest reduction in casein kinase 1 alpha (CK1α) by lenalidomide contributes to its clinical effectiveness in treating del(5q) myelodysplastic syndrome. However, the mechanism by which CK1α impacts lymphoma survival remains inadequately defined. We developed INNO-220, a CRBN-dependent CK1α degrader, by leveraging cytokine expression profiling in T cells. Unlike lenalidomide, INNO-220 is a highly selective and potent degrader of CK1α without affecting IKZF1/3. Screening across lymphoma cell lines revealed that cells harboring wild-type p53 and exhibiting constitutive NF-κB signaling were particularly sensitive to CK1α degradation yet resistant to Bruton tyrosine kinase inhibitors. Moreover, INNO-220 suppresses NF-κB signaling and activates p53 pathway, leading to complete inhibition of lymphoma tumor growth in vivo. Mechanistically, INNO-220 disrupts the assembly and function of the CARD11/BCL10/MALT1 complex, thereby inhibiting NF-κB signaling in stimulated T cells and lymphoma cells that harbor an activating mutation in CARD11. Moreover, we observed that activation of wild-type p53 upon INNO-220 treatment was sufficient to induce potent cancer cell death even in the absence of constitutive NF-κB activity. In summary, our findings introduce a selective CK1α degrader as a novel therapeutic approach for lymphoma, providing both mechanistic insights and a potential patient selection strategy in treating lymphoma and possibly other cancers.