Exploring Five-Membered S -Heterocyclic Scaffolds As Novel CaMKIIα Ligands Targeting the Hub Domain
Ludovica Stella Sirocchi, Francesco Bavo, Stine Juul Gauger, Ole Huld Jacobsen, Louise Thiesen, Simona Mattiussi, Elena Martino, Christoffer Bundgaard, Petrine Wellendorph, Bente FrølundAbstract
The Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. In continuation of our efforts exploiting the CaMKIIα hub domain representing the high-affinity target of γ-hydroxybutyrate (GHB), we herein report a study on five-membered heterocycles related to 2-(2,6-dichlorophenyl)thiazole-4-carboxylic acid (PTCA), a low nanomolar-affinity ligand for the CaMKIIα hub domain. To explore the chemical scaffold without adversely affecting physicochemical parameters, we expanded the diversity of compounds by introducing a higher degree of saturation and chirality. A distinct preference for the presence and positioning of the sulfur atom in relation to the 4-carboxylic acid was observed together with stereoselective recognition patterns. The midnanomolar-affinity ligands 2 and 3a showed good cellular permeability which is vital for in vivo studies, and importantly, no efflux transporter substrate effect was observed.