Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Aberrant
activation of Bruton’s tyrosine kinase (BTK) plays
an important role in pathogenesis of B-cell lymphomas, suggesting
that inhibition of BTK is useful in the treatment of hematological
malignancies. The discovery of a more selective on-target covalent
BTK inhibitor is of high value. Herein, we disclose the discovery
and preclinical characterization of a potent, selective, and irreversible
BTK inhibitor as our clinical candidate by using in vitro potency,
selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for
prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and
excellent selectivity over other TEC, EGFR and Src family kinases,
(ii) desirable ADME, excellent in vivo pharmacodynamic in mice and
efficacy in OCI-LY10 xenograft models.