Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2)

CaMKK2 signals through AMPK-dependent and AMPK-independent
pathways
to trigger cellular outputs including proliferation, differentiation,
and migration, resulting in changes to metabolism, bone mass accrual,
neuronal function, hematopoiesis, and immunity. CAMKK2 is upregulated
in tumors including hepatocellular carcinoma, prostate, breast, and
gastric cancer, and genetic deletion in myeloid cells results in increased
antitumor immunity in several syngeneic models. Validation of the
biological roles of CaMKK2 has relied on genetic deletion or small
molecule inhibitors with activity against several biological targets.
We sought to generate selective inhibitors and degraders to understand
the biological impact of inhibiting catalytic activity and scaffolding
and the potential therapeutic benefits of targeting CaMKK2. We report
herein selective, ligand-efficient inhibitors and ligand-directed
degraders of CaMKK2 that were used to probe immune and tumor intrinsic
biology. These molecules provide two distinct strategies for ablating
CaMKK2 signaling in vitro and in vivo.