TY - JOUR
T1 - Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes
AU - Eduful, Benjamin J.
AU - O'Byrne, Sean N.
AU - Temme, Louisa
AU - Asquith, Christopher R.M.
AU - Liang, Yi
AU - Picado, Alfredo
AU - Pilotte, Joseph R.
AU - Hossain, Mohammad Anwar
AU - Wells, Carrow I.
AU - Zuercher, William J.
AU - Catta-Preta, Carolina M.C.
AU - Zonzini Ramos, Priscila
AU - Santiago, André De S.
AU - Couñago, Rafael M.
AU - Langendorf, Christopher G.
AU - Nay, Kévin
AU - Oakhill, Jonathan S.
AU - Pulliam, Thomas L.
AU - Lin, Chenchu
AU - Awad, Dominik
AU - Willson, Timothy M.
AU - Frigo, Daniel E.
AU - Scott, John W.
AU - Drewry, David H.
N1 - Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/8/12
Y1 - 2021/8/12
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.0c02274
DO - 10.1021/acs.jmedchem.0c02274
M3 - Article
C2 - 34264658
AN - SCOPUS:85111503841
SN - 0022-2623
VL - 64
SP - 10849
EP - 10877
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 15
ER -