2. Academic Validation
  3. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer

Bruton tyrosine kinase degradation as a therapeutic strategy for cancer

  • Blood. 2019 Feb 28;133(9):952-961. doi: 10.1182/blood-2018-07-862953.
Dennis Dobrovolsky 1 2 3,  Eric S Wang 2 3,  Sara Morrow 4,  Catharine Leahy 4,  Tyler Faust 2 3,  Radosław P Nowak 2 3,  Katherine A Donovan 2 3,  Guang Yang 4 5,  Zhengnian Li 2 3,  Eric S Fischer 2 3,  Steven P Treon 4 5 6,  David M Weinstock 4 7,  Nathanael S Gray 2 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston MA.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • 4 Department of Medical Oncology and.
  • 5 Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA.
  • 6 Department of Medicine, Harvard Medical School, Boston, MA; and.
  • 7 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
PMID: 30545835 DOI: 10.1182/blood-2018-07-862953
Abstract

The covalent Bruton tyrosine kinase (Btk) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it is not selective for Btk, and multiple mechanisms of resistance, including the C481S-BTK mutation, can compromise its efficacy. We hypothesized that small-molecule-induced Btk degradation may overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that Btk degradation results in potent suppression of signaling and proliferation in Cancer cells and that Btk degraders efficiently degrade C481S-BTK. Moreover, we discovered DD-03-171, an optimized lead compound that exhibits enhanced antiproliferative effects on mantle cell lymphoma (MCL) cells in vitro by degrading Btk, IKFZ1, and IKFZ3 as well as efficacy against patient-derived xenografts in vivo. Thus, "triple degradation" may be an effective therapeutic approach for treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and Other B-cell lymphomas.

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