Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Bruton’s tyrosine kinase (BTK) is a Tec family
kinase that
plays an essential role in B-cell receptor (BCR) signaling as well
as Fcγ receptor signaling in leukocytes. Pharmacological inhibition
of BTK has been shown to be effective in treating hematological malignancies
and is hypothesized to provide an effective strategy for the treatment
of autoimmune diseases such as rheumatoid arthritis and systemic lupus
erythematosus. We report the discovery and preclinical properties
of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor
with potent whole blood activity and exceptional kinome selectivity.
JNJ-64264681 demonstrated excellent oral efficacy in both cancer and
autoimmune models with sustained in vivo target coverage amenable
to once daily dosing and has advanced into human clinical studies
to investigate safety and pharmacokinetics.