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Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes

DOI: 10.1021/acs.jmedchem.0c02274 DOI Help

Authors: Benjamin J. Eduful (University of North Carolina at Chapel Hill) , Sean N. O'Byrne (University of North Carolina at Chapel Hill) , Louisa Temme (University of North Carolina at Chapel Hill) , Christopher R. M. Asquith (University of North Carolina at Chapel Hill) , Yi Liang (University of North Carolina at Chapel Hill) , Alfredo Picado (University of North Carolina at Chapel Hill) , Joseph R. Pilotte (University of North Carolina at Chapel Hill) , Mohammad Anwar Hossain (University of North Carolina at Chapel Hill) , Carrow I. Wells (University of North Carolina at Chapel Hill) , William J. Zuercher (University of North Carolina at Chapel Hill) , Carolina M. C. Catta-Preta (Universidade Estadual de Campinas (UNICAMP)) , Priscila Zonzini Ramos (Universidade Estadual de Campinas (UNICAMP)) , André De S. Santiago (Universidade Estadual de Campinas (UNICAMP)) , Rafael M. Counago (Universidade Estadual de Campinas (UNICAMP)) , Christopher G. Langendorf (The University of Melbourne) , Kévin Nay (The University of Melbourne; Australian Catholic University) , Jonathan S. Oakhill (The University of Melbourne; Australian Catholic University) , Thomas L. Pulliam (University of Texas MD Anderson Cancer Center; University of Houston) , Chenchu Lin (University of Texas MD Anderson Cancer Center; University of Houston) , Dominik Awad (University of Texas MD Anderson Cancer Center; University of Houston) , Timothy M. Willson (University of North Carolina at Chapel Hill) , Daniel E. Frigo (University of Texas MD Anderson Cancer Center; University of Houston; The Methodist Hospital Research Institute) , John W. Scott (The University of Melbourne; Australian Catholic University; The Florey Institute of Neuroscience and Mental Health) , David H. Drewry (University of North Carolina at Chapel Hill)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 8

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 10619

Open Access Open Access

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.

Journal Keywords: Inhibitors; Inhibition; Organic compounds; Peptides and proteins; Phenyls

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 17/07/2021 21:34

Documents:
acs.jmedchem.0c02274.pdf

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)