Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes
Journal article
Eduful, Benjamin J., O'Byrne, Sean N., Temme, Louisa, Asquith, Christopher R. M., Liang, Yi, Picado, Alfredo, Pilotte, Joseph R., Hossain, Mohammad Anwar, Wells, Carrow I., Zuercher, William J., Catta-Preta, Carolina M.C, Ramos, Priscila, de S. Santiago, André, Counago, Rafael M., Langendorf, Christopher G., Nay, Kevin, Oakhill, Jonathan S., Pulliam, Thomas L., Lin, Chenchu, ... Drewry, David H.. (2021). Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes. Journal of Medicinal Chemistry. 64(15), pp. 10849-10877. https://doi.org/10.1021/acs.jmedchem.0c02274
Authors | Eduful, Benjamin J., O'Byrne, Sean N., Temme, Louisa, Asquith, Christopher R. M., Liang, Yi, Picado, Alfredo, Pilotte, Joseph R., Hossain, Mohammad Anwar, Wells, Carrow I., Zuercher, William J., Catta-Preta, Carolina M.C, Ramos, Priscila, de S. Santiago, André, Counago, Rafael M., Langendorf, Christopher G., Nay, Kevin, Oakhill, Jonathan S., Pulliam, Thomas L., Lin, Chenchu, Awad, Dominik, Willson, Timothy M., Frigo, Daniel E., Scott, John Walter W. and Drewry, David H. |
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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. |
Year | 2021 |
Journal | Journal of Medicinal Chemistry |
Journal citation | 64 (15), pp. 10849-10877 |
Publisher | American Chemical Society |
ISSN | 0022-2623 |
Digital Object Identifier (DOI) | https://doi.org/10.1021/acs.jmedchem.0c02274 |
PubMed ID | 34264658 |
Scopus EID | 2-s2.0-85111503841 |
PubMed Central ID | PMC8365604 |
Open access | Published as ‘gold’ (paid) open access |
Research or scholarly | Research |
Page range | 10849-10877 |
Funder | National Health and Medical Research Council (NHMRC) |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 15 Jul 2021 |
Publication process dates | |
Deposited | 18 Nov 2021 |
Grant ID | NHMRC/1138102 |
NHMRC/1145265 | |
NHMRC/1143080 |
https://acuresearchbank.acu.edu.au/item/8x148/hinge-binder-scaffold-hopping-identifies-potent-calcium-calmodulin-dependent-protein-kinase-kinase-2-camkk2-inhibitor-chemotypes
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Publisher's version
OA_Eduful_2021_Hinge_binder_scaffold_hopping_identifies_potent.pdf | |
License: CC BY-NC-ND 4.0 | |
File access level: Open |
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