Discovery of a Potent, Covalent BTK Inhibitor for B‑Cell Lymphoma

BTK is a member of the TEC family
of non-receptor tyrosine kinases
whose deregulation has been implicated in a variety of B-cell-related
diseases. We have used structure-based drug design in conjunction
with kinome profiling and cellular assays to develop a potent, selective,
and irreversible BTK kinase inhibitor, QL47, which covalently modifies
Cys481. QL47 inhibits BTK kinase activity with an IC50 of
7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with
an EC50 of 475 nM, and inhibits phosphorylation of a downstream
effector PLCγ2 (Tyr759) with an EC50 of 318 nM. In
Ramos cells QL47 induces a G1 cell cycle arrest that is associated
with pronounced degradation of BTK protein. QL47 inhibits the proliferation
of B-cell lymphoma cancer cell lines at submicromolar concentrations.