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

Benjamin J. Eduful, Sean N. O'Byrne, Louisa Temme, Christopher R.M. Asquith, Yi Liang, Alfredo Picado, Joseph R. Pilotte, Mohammad Anwar Hossain, Carrow I. Wells, William J. Zuercher, Carolina M.C. Catta-Preta, Priscila Zonzini Ramos, André De S. Santiago, Rafael M. Couñago, Christopher G. Langendorf, Kévin Nay, Jonathan S. Oakhill, Thomas L. Pulliam, Chenchu Lin, Dominik AwadTimothy M. Willson, Daniel E. Frigo, John W. Scott, David H. Drewry

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10849-10877
Number of pages29
JournalJournal of Medicinal Chemistry
Volume64
Issue number15
DOIs
StatePublished - Aug 12 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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