Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain. / Tian, Yongsong; Shehata, Mohamed A.; Gauger, Stine Juul; Ng, Clarissa K.L.; Solbak, Sara; Thiesen, Louise; Bruus-Jensen, Jesper; Krall, Jacob; Bundgaard, Christoffer; Gibson, K. Michael; Wellendorph, Petrine; Frølund, Bente.
In: Journal of Medicinal Chemistry, Vol. 65, No. 9, 2022, p. 6656-6676.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain
AU - Tian, Yongsong
AU - Shehata, Mohamed A.
AU - Gauger, Stine Juul
AU - Ng, Clarissa K.L.
AU - Solbak, Sara
AU - Thiesen, Louise
AU - Bruus-Jensen, Jesper
AU - Krall, Jacob
AU - Bundgaard, Christoffer
AU - Gibson, K. Michael
AU - Wellendorph, Petrine
AU - Frølund, Bente
N1 - Publisher Copyright: © 2022 American Chemical Society.
PY - 2022
Y1 - 2022
N2 - The Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac (3). Herein, we employed in silico approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with 3. The oxygen-bridged analogue 4d showed mid-nanomolar affinity and notable ligand-induced stabilization effects toward the CaMKIIα hub oligomer. Importantly, 4d displayed superior chemical and metabolic stability over 3 by showing excellent chemical stability in phosphate-buffered saline and high resistance to form reactive intermediates and subsequent sulfur conjugates. Altogether, our study highlights 4d as a new CaMKIIα hub high-affinity ligand with enhanced pharmacokinetic properties, representing a powerful tool compound for allosteric regulation of kinase activity with subtype specificity.
AB - The Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac (3). Herein, we employed in silico approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with 3. The oxygen-bridged analogue 4d showed mid-nanomolar affinity and notable ligand-induced stabilization effects toward the CaMKIIα hub oligomer. Importantly, 4d displayed superior chemical and metabolic stability over 3 by showing excellent chemical stability in phosphate-buffered saline and high resistance to form reactive intermediates and subsequent sulfur conjugates. Altogether, our study highlights 4d as a new CaMKIIα hub high-affinity ligand with enhanced pharmacokinetic properties, representing a powerful tool compound for allosteric regulation of kinase activity with subtype specificity.
U2 - 10.1021/acs.jmedchem.1c02177
DO - 10.1021/acs.jmedchem.1c02177
M3 - Journal article
C2 - 35500061
AN - SCOPUS:85129931274
VL - 65
SP - 6656
EP - 6676
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 9
ER -
ID: 312028949