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

Yamit Shorer Arbel, Ben Zion Katz, Ronen Gabizon, Yotam Bronstein, Talia Kamdjou, Anat Globerson Levin, Chava Perry, Irit Avivi, Nir London, Yair Herishanu, Amit Shraga

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number646971
JournalFrontiers in Oncology
Volume11
DOIs
StatePublished - 13 May 2021

Keywords

  • BCR (B cell receptor) signaling
  • BTK - Bruton’s tyrosine kinase
  • CLL (Chronic Lymphocytic Leukemia)
  • PROTACs (proteolysis targeting chimeras)
  • ibrutinib

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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