The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) activates CAMK1, CAMK4, AMPK, and AKT, leading to numerous physiological responses. The deregulation of CAMKK2 is linked to several diseases, suggesting the utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work, we demonstrate that STO-609, frequently described as a selective inhibitor for CAMKK2, potently inhibits a significant number of other kinases. Through an analysis of literature and public databases, we have identified other potent CAMKK2 inhibitors and verified their activities in differential scanning fluorimetry and enzyme inhibition assays. These inhibitors are potential starting points for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology.
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.
We have determined that tetrahydroindazoles such as show potent activity against, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of have previously been explored, we present here our efforts to optimize their activity against via the synthesis of novel analogues designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue, specifically through the auspices of functionalization of an amine embedded into the scaffold.
The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.
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