Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton’s Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases

Bruton’s
tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent
role in the treatment of B cell malignancies. However, further refinement
is needed to this class of agents, particularly in terms of adverse
events (potentially driven by kinase promiscuity), which preclude
their evaluation in nononcology indications. Here, we report the discovery
and preclinical characterization of evobrutinib, a potent, obligate
covalent inhibitor with high kinase selectivity. Evobrutinib displayed
sufficient preclinical pharmacokinetic and pharmacodynamic characteristics
which allowed for in vivo evaluation in efficacy models. Moreover,
the high selectivity of evobrutinib for BTK over epidermal growth
factor receptor and other Tec family kinases suggested a low potential
for off-target related adverse effects. Clinical investigation of
evobrutinib is ongoing in several autoimmune diseases, including multiple
sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.