In Silico Identification of a Novel Hinge-Binding Scaffold for Kinase Inhibitor Discovery

To explore novel kinase hinge-binding
scaffolds, we carried out
structure-based virtual screening against p38α MAPK as a model
system. With the assistance of developed kinase-specific structural
filters, we identify a novel lead compound that selectively inhibits
a panel of kinases with threonine as the gatekeeper residue, including
BTK and LCK. These kinases play important roles in lymphocyte activation,
which encouraged us to design novel kinase inhibitors as drug candidates
for ameliorating inflammatory diseases and cancers. Therefore, we
chemically modified our substituted triazole-class lead compound to
improve the binding affinity and selectivity via a “minimal
decoration” strategy, which resulted in potent and selective
kinase inhibitors against LCK (18 nM) and BTK (8 nM). Subsequent crystallographic
experiments validated our design. These rationally designed compounds
exhibit potent on-target inhibition against BTK in B cells or LCK
in T cells, respectively. Our work demonstrates that structure-based
virtual screening can be applied to facilitate the development of
novel chemical entities in crowded chemical space in the field of
kinase inhibitor discovery.