SGC-CAMKK2-1: A Chemical Probe for CAMKK2

Abstract

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.

Dihydroartemisinin inhibits liver cancer cell migration and invasion by reducing ATP synthase production through CaMKK2/NCLX

“…Mitochondrial calcium-regulating proteins affect cellular energy metabolism by activating oxidative metabolism, mitochondrial respiration and ATP synthesis (32,33). CaMKK2 and NCLX serve important roles in physiological or pathological processes, such as maintaining cellular energy homeostasis and cell proliferation (34,35). In the study of gastric cancer, the application of small molecule inhibitors of calcium-regulated protein can significantly inhibit the peritoneal metastasis of gastric cancer cells (36).…”

CaMKK2 is not involved in contraction-stimulated AMPK activation and glucose uptake in skeletal muscle

“…Ionomycin and STO-609 were purchased from Tocris. SGC-CAMKK2-1 and SGC-CAMKK2-1 compounds were synthesized as described [ 28 ]. All other reagents were from MerckMilliporeSigma unless otherwise stated.…”

“…In the current study, we aimed to address these limitations and establish whether CaMKK2 functions as an upstream activator of AMPK in response to contractions and mediates contraction-stimulated glucose uptake in skeletal muscle. To this end, we employed a recently developed potent and selective CaMKK2 inhibitor alongside a structurally related but inactive compound [ 28 ], as well as CaMKK2 KO mice.…”

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

“…More recently, a CaMKK2 chemical probe SGC-CAMKK2−1 based on a furopyridine core was reported, with improved kinome selectivity. 21 At the onset of our work, we took a similar core hopping approach that resulted in the identification of a complementary quinazoline scaffold. Considering the potential therapeutic value of modulating CaMKK2 biology and the current limitations in our understanding, we sought to develop highly potent and selective CaMKK2 inhibitors with favorable physiochemical properties, to probe CaMKK2 biology in vitro and in vivo.…”

“…These efforts resulted in multiple published crystal structures and chemical starting points for next-generation CaMKK2 inhibitors. More recently, a CaMKK2 chemical probe SGC-CAMKK2–1 based on a furopyridine core was reported, with improved kinome selectivity . At the onset of our work, we took a similar core hopping approach that resulted in the identification of a complementary quinazoline scaffold.…”