Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes

CAMKK2 is a serine/threonine
kinase and an activator of AMPK whose
dysregulation is linked with multiple diseases. Unfortunately, STO-609,
the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations.
To identify promising scaffolds as starting points for the development
of high-quality CAMKK2 chemical probes, we utilized a hinge-binding
scaffold hopping strategy to design new CAMKK2 inhibitors. Starting
from the potent but promiscuous disubstituted 7-azaindole GSK650934,
a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused
heteroaromatic cores, were synthesized. The compound set was specifically
designed to probe interactions with the kinase hinge-binding residues.
Compared to GSK650394 and STO-609, 13 compounds displayed similar
or better CAMKK2 inhibitory potency in vitro, while
compounds 13g and 45 had improved selectivity
for CAMKK2 across the kinome. Our systematic survey of hinge-binding
chemotypes identified several potent and selective inhibitors of CAMKK2
to serve as starting points for medicinal chemistry programs.