posted on 2019-09-12, 13:33authored byRobert Pulz, Daniela Angst, Janet Dawson, Francois Gessier, Sascha Gutmann, Rene Hersperger, Alexandra Hinniger, Philipp Janser, Guido Koch, Laszlo Revesz, Anna Vulpetti, Rudolf Waelchli, Alfred Zimmerlin, Bruno Cenni
Bruton’s
tyrosine kinase (BTK) is a member of the TEC kinase
family and is selectively expressed in a subset of immune cells. It
is a key regulator of antigen receptor signaling in B cells and of
Fc receptor signaling in mast cells and macrophages. A BTK inhibitor
will likely have a positive impact on autoimmune diseases which are
caused by autoreactive B cells and immune-complex driven inflammation.
We report the design, optimization, and characterization of potent
and selective covalent BTK inhibitors. Starting from the selective
reversible inhibitor 3 binding to an inactive conformation
of BTK, we designed covalent irreversible compounds by attaching an
electrophilic warhead to reach Cys481. The first prototype 4 covalently modified BTK and showed an excellent kinase selectivity
including several Cys-containing kinases, validating the design concept.
In addition, this compound blocked FcγR-mediated hypersensitivity in vivo. Optimization of whole blood potency and metabolic
stability resulted in compounds such as 8, which maintained
the excellent kinase selectivity and showed improved BTK occupancy in vivo.