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BTK Inhibition and the Mechanism of Action of Ibrutinib

Jennifer Woyach, MD
Published Online:7:32 PM, Tue August 20, 2013


Jennifer Woyach, MD, Assistant Professor of Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, discusses Bruton's tyrosine kinase (BTK) inhibition and the mechanism of action of ibrutinib.

BTK is not found to be recurrently mutated in chronic lymphocytic leukemia‎ (CLL), but it is overexpressed at the transcript level. At the protein level, Woyach says, it is slightly more variable but is seen to be overexpressed in many patients. BTK and other members of the pathway are constitutively phosphorylated in this disease, likely causing activation and accumulation of downstream targets.

Ibrutinib binds to BTK at the cysteine-481 residue, which is in the active site, preventing kinase activity of BTK. Ibrutinib is an irreversible covalent inhibitor, meaning that after the drug is metabolized, BTK should still be inhibited.

Clinical Pearls

  • BTK is not found to be recurrently mutated in CLL, but it is overexpressed at the transcript level in CLL
  • BTK and other members of the pathway are constitutively phosphorylated, likely causing activation of downstream targets

Clinical Pearls II

  • Ibrutinib binds to BTK at the cysteine-481 residue
  • Ibrutinib is an irreversible covalent inhibitor
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