A Small Molecule Inhibitor of Bruton’s Tyrosine Kinase Involved in B‑Cell Signaling

Protein
kinases are fundamental within almost all cellular signal
transduction networks. Among these, Bruton’s tyrosine kinase
(Btk), which belongs to the Tec family of proteins, plays an imperative
part in B-cell signaling. Owing to its role, Btk has been established
as an important therapeutic target for a vast range of disorders related
to B-cell development and function, such as the X-linked agammaglobulinemia,
various B-cell malignancies, inflammation, and autoimmune diseases.
Herein, using computer-based screening of a library of 20 million
small molecules, we identified a small molecule capable of directly
binding the Btk kinase domain. On the basis of this hit compound,
we conducted a focused structure-similarity search to explore the
effect of different chemical modifications on binding toward Btk.
This search identified the molecule N2,N6-bis­(2,3-dihydrobenzo­[b]­[1,4]­dioxin-6-yl)-9H-purine-2,6-diamine as a potent inhibitor of Btk. The latter
small molecule binds Btk with a dissociation constant of 250 nM and
inhibits Btk activity both in vitro and in-cell.