Kinase Crystal Miner: A Powerful Approach to Repurposing 3D Hinge Binding Fragments and Its Application to Finding Novel Bruton Tyrosine Kinase Inhibitors

Protein kinases represent an important
target class for drug discovery
because of their role in signaling pathways involved in disease areas
such as oncology and immunology. A key element of many ATP-competitive
kinase inhibitors is their hinge-binding motif. Here, we describe
Kinase Crystal Miner (KCM)a new approach developed at Boehringer
Ingelheim (BI) that harvests the existing crystallographic information
on kinase-inhibitor co-crystal structures from internal and external
databases. About 1000 unique three-dimensional kinase inhibitor hinge
binding motifs have been extracted from structures covering more than
180 different protein kinases. These hinge binding motifs along with
their attachment vectors have been combined in the KCM for the purpose
of scaffold hopping, kinase screening deck design, and interactive
structure-based design. Prospective scaffold hopping using the KCM
identified two potent and selective Bruton tyrosine kinase (BTK) inhibitors
with hinge binding fragments novel to BTK.