Proteolysis Targeting Chimeras for BTK Efficiently Inhibit B-Cell Receptor Signaling and Can Overcome Ibrutinib Resistance in CLL Cells.

Autor:	Shorer Arbel Y; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel., Katz BZ; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.; Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Gabizon R; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel., Shraga A; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel., Bronstein Y; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel., Kamdjou T; Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Globerson Levin A; Immunology Research Laboratory, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Perry C; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.; Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Avivi I; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.; Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., London N; Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel., Herishanu Y; Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.; Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2021 May 13; Vol. 11, pp. 646971. Date of Electronic Publication: 2021 May 13 (Print Publication: 2021).
DOI:	10.3389/fonc.2021.646971
Abstrakt:	Proteolysis targeting chimeras (PROTACs) are small molecules that form ternary complexes between their target and E3 ligase, resulting in ubiquitination and proteasomal degradation of the target protein. Using our own designed Bruton's tyrosine kinase (BTK) PROTAC compounds, we show herein efficient BTK degradation in chronic lymphocytic leukemia (CLL) cells. The reversible non-covalent compound (NC-1) was the most potent and therefore we focused on this PROTAC to investigate its subsequent effects on the BCR pathway. NC-1 decreased baseline BTK phosphorylation as well as activation of BTK and other signaling molecules downstream of the BCR pathway, following IgM engagement. These effects were also obtained in samples from CLL patients with clinical resistance to ibrutinib and mutations at C481. NC-1 treatment further decreased baseline CD69 surface levels, completely abrogated its upregulation following IgM activation, decreased CLL cells migration toward SDF-1 and overcame stromal anti-apoptotic protection. In conclusion, our results indicate that targeting BTK using the PROTAC strategy could be a potential novel therapeutic approach for CLL. Competing Interests: YH received honoraria from AstraZeneca and Janssen for work unrelated to the present study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Shorer Arbel, Katz, Gabizon, Shraga, Bronstein, Kamdjou, Globerson Levin, Perry, Avivi, London and Herishanu.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu