Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase for B‑Cell Malignancies and Autoimmune Diseases

Bruton’s
tyrosine kinase (BTK) plays an essential role in
B-cell receptor (BCR)-mediated signaling as well as the downstream
signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell
malignancies by interfering with BCR signaling has been clinically
validated by some covalent inhibitors, but suboptimal kinase selectivity
may lead to some adverse effects, which also makes the clinical development
of autoimmune disease therapy more challenging. The structure–activity
relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors,
in which BGB-8035 is located in the ATP
binding pocket and has similar hinge binding to ATP but exhibits high
selectivity over other kinases (EGFR, Tec, etc.). With an excellent
pharmacokinetic profile as well as demonstrated efficacy studies in
oncology and autoimmune disease models, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to
that of BGB-3111.