Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain

  • J Med Chem. 2022 May 12;65(9):6656-6676. doi: 10.1021/acs.jmedchem.1c02177.
Yongsong Tian  1 ,  Mohamed A Shehata  1 ,  Stine Juul Gauger  1 ,  Clarissa K L Ng  1 ,  Sara Solbak  1 ,  Louise Thiesen  1 ,  Jesper Bruus-Jensen  1 ,  Jacob Krall  1 ,  Christoffer Bundgaard  2 ,  K Michael Gibson  3 ,  Petrine Wellendorph  1 ,  Bente Frølund  1
Affiliations
  • 1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 2. Translational DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
  • 3. Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington 99202, United States.
PMID: 35500061 DOI: 10.1021/acs.jmedchem.1c02177
Abstract

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.

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