GDC-0853 inhibits both wild type and C481S BTK variants while preserving NK cell mediated ADCC
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Date
2016-02
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Abstract
Bruton's tyrosine kinase (BTK) has recently emerged as an attractive therapeutic target in hematologic malignancies. Ibrutinib, the first in class BTK inhibitor, improves survival and is well tolerated in patients. Here, we investigate a novel BTK inhibitor, GDC-0853, to evaluate its efficacy in chronic lymphocytic leukemia (CLL). GDC-0853 is unique among BTK inhibitors in that it utilizes a novel allosteric binding site, different from the C481 kinase domain to which ibrutinib irreversibly binds. Like ibrutinib, GDC-0853 blocks B cell receptor signaling, modestly reduces viability, prevents stromal and cytokine induced survival, and limits activation in CLL lymphocytes through the inhibition of BTK. We found that due to its novel site of action, GDC-0853 also inhibits C481S mutated BTK in an in vitro system. GDC-0853 is more selective for BTK than is ibrutinib which also irreversibly inhibits interleukin-2 inducible kinase (ITK), a Tec kinase responsible for T and NK cell activation. The selectivity of GDC-0853 preserves ITK function in T and NK cells. Unlike ibrutinib, upper-physiologic concentrations of GDC-0853 had no effect on T cell activation or NK cell antibody dependent cell mediated cytotoxicity (ADCC). Our results indicate that the GDC-0853 may be an effective therapy for use in CLL as monotherapy or in combination with anti-CD20 antibodies, especially among the emerging population of patients who are resistant to first generation BTK inhibitors.
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Professional Biological Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Cancer, Leukemia, Chronic lymphocytic leukemia, Bruton's tyrosine kinase, GDC-0853, Ibrutinib