A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia
Abstract
:1. Introduction
2. Results
2.1. SRX3305 Inhibits Proliferation and Induces Apoptosis of Malignant B-Cell Lines
2.2. SRX3305 Inhibits Critical BCR Survival Signaling in CLL
2.3. SRX3305 Inhibits Primary Malignant B-Cell Survival and Proliferation
2.4. SRX3305 Disrupts Stroma Survival Support and Chemokine-Induced Migration in CLL
2.5. SRX3305 Is Active in Ibrutinib-Resistant CLL
3. Discussion
4. Materials and Methods
4.1. Cell Lines, Primary Samples, and Inhibitors
4.2. Cell Culture
4.3. Cytotoxicity and Flow Cytometric Studies
4.4. BCR Pathway Activation
4.5. Inhibitor Washout Assay
4.6. Ex Vivo Stimulation of Primary Malignant B-Cells
4.7. Immunoblot Analyses
4.8. Migration Assay
4.9. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Smith, A.L.; Eiken, A.P.; Skupa, S.A.; Moore, D.Y.; Umeta, L.T.; Smith, L.M.; Lyden, E.R.; D’Angelo, C.R.; Kallam, A.; Vose, J.M.; et al. A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia. Int. J. Mol. Sci. 2022, 23, 6712. https://doi.org/10.3390/ijms23126712
Smith AL, Eiken AP, Skupa SA, Moore DY, Umeta LT, Smith LM, Lyden ER, D’Angelo CR, Kallam A, Vose JM, et al. A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia. International Journal of Molecular Sciences. 2022; 23(12):6712. https://doi.org/10.3390/ijms23126712
Chicago/Turabian StyleSmith, Audrey L., Alexandria P. Eiken, Sydney A. Skupa, Dalia Y. Moore, Lelisse T. Umeta, Lynette M. Smith, Elizabeth R. Lyden, Christopher R. D’Angelo, Avyakta Kallam, Julie M. Vose, and et al. 2022. "A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia" International Journal of Molecular Sciences 23, no. 12: 6712. https://doi.org/10.3390/ijms23126712