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A highly selective and orally bioavailable casein kinase 1 alpha degrader through p53 signaling pathway targets
Shi Feng1, Ran Kong2, Cong Wang2
1School of Pharmaceutical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Abstract:
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.
Insights
A novel therapeutic agent, INNO-220, selectively degrades casein kinase 1 alpha (CK1α), effectively inhibiting lymphoma growth by suppressing NF-κB signaling and activating the p53 pathway.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Lenalidomide's modest reduction of casein kinase 1 alpha (CK1α) aids del(5q) myelodysplastic syndrome treatment, but CK1α's role in lymphoma survival is unclear.
- Understanding CK1α's mechanism in lymphoma is crucial for developing targeted therapies.
Purpose of the Study:
- To develop a selective CK1α degrader for lymphoma treatment.
- To elucidate the mechanism of CK1α degradation in lymphoma cells.
- To identify patient populations sensitive to CK1α-targeted therapy.
Main Methods:
- Development of INNO-220, a CRBN-dependent CK1α degrader, through cytokine expression profiling.
- Screening of lymphoma cell lines for sensitivity to CK1α degradation.
- In vivo studies to assess INNO-220's efficacy in inhibiting lymphoma tumor growth.
- Mechanistic studies involving NF-κB and p53 pathway analysis and CARD11/BCL10/MALT1 complex disruption.
Main Results:
- INNO-220 selectively degrades CK1α without affecting IKZF1/3, unlike lenalidomide.
- Lymphoma cells with wild-type p53 and constitutive NF-κB signaling are sensitive to INNO-220.
- INNO-220 suppresses NF-κB signaling, activates the p53 pathway, and inhibits lymphoma tumor growth in vivo.
- INNO-220 disrupts the CARD11/BCL10/MALT1 complex, inhibiting NF-κB signaling.
Conclusions:
- Selective CK1α degradation represents a novel therapeutic strategy for lymphoma.
- INNO-220 demonstrates potent anti-lymphoma activity through NF-κB suppression and p53 activation.
- Findings provide mechanistic insights and a potential patient selection strategy for CK1α-targeted lymphoma therapy.
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