Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes
Year: 2026
Type: article
Abstract: 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.
Source: UNC Libraries
DOI: 10.17615/8fn2-ay24
Authors: Asquith, Christopher R. M., Frigo, Daniel E., Zuercher, William J., Langendorf, Christopher G., Pilotte, Joseph R., de S. Santiago, André, Awad, Dominik, Temme, Louisa, Drewry, David H., Wells, Carrow I., Couñago, Rafael M., Picado, Alfredo, Ramos, Priscila Zonzini, Pulliam, Thomas L., Eduful, Benjamin J., Oakhill, Jonathan S., Willson, Timothy M., Liang, Yi, Catta-Preta, Carolina M. C., O’Byrne, Sean N., Nay, Kévin, Hossain, Mohammad Anwar, Scott, John W., Lin, Chenchu
Institution: University of North Carolina at Chapel Hill
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: green
Funders: Genome Canada, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Directorate for Mathematical and Physical Sciences, Office of Science, Takeda Oncology, National Health and Medical Research Council, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Argonne National Laboratory
OpenAlex ID: W7213408389
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