Gaining Insights into Key Structural Hotspots within the Allosteric Binding Pockets of Protein Kinases.

Protein kinases are essential regulators of cell function and represent one of the largest and most diverse protein families. They are particularly influential in signal transduction and coordinating complex processes like the cell cycle. Out of the 518 human protein kinases identified, 478 are part of a single superfamily sharing catalytic domains that are related in sequence. The dysregulation of protein kinases due to certain mutations has been associated with various diseases, including cancer. Although most of the protein kinase inhibitors identified as type I or type II primarily target the ATP-binding pockets of kinases, the structural and sequential resemblances among these pockets pose a significant challenge for selective inhibition. Therefore, targeting allosteric pockets that are beside highly conserved ATP pockets has emerged as a promising strategy to prevail current limitations, such as poor selectivity and drug resistance. In this article, we compared the binding pockets of various protein kinases for which allosteric (type III) inhibitors have already been developed. Additionally, understanding the structure and shape of existing ligands could aid in identifying key interaction sites within the allosteric pockets of kinases. This comprehensive review aims to facilitate the design of more effective and selective allosteric inhibitors.

Targeting the CSF-1/CSF-1R Axis: Exploring the Potential of CSF1R Inhibitors in Neurodegenerative Diseases.

We report herein the potential of colony-stimulating factor-1 receptor (CSF1R) inhibitors as therapeutic agents in neuroinflammatory diseases, with a focus on Alzheimer's disease (AD). Employing a carefully modified scaffold, N-(4-heterocycloalkyl-2-cycloalkylphenyl)-5-methylisoxazole-3-carboxamide, we identify highly selective and potent CSF1R inhibitors─7dri and 7dsi. Molecular docking studies shed light on the binding modes of these key compounds within the CSF1R binding site. Remarkably, kinome-wide selectivity assessment underscores the impressive specificity of 7dri for CSF-1R. Notably, 7dri emerges as a potent CSF-1R inhibitor with favorable cellular activity and minimal cytotoxicity among the synthesized compounds. Demonstrating efficacy in inhibiting CSF1R phosphorylation in microglial cells and successfully mitigating neuroinflammation in an in vivo LPS-induced model, 7dri establishes itself as a promising antineuroinflammatory agent.

Cu(ii)-BODIPY photosensitizer for CAIX overexpressed cancer stem cell therapy.

Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(ii), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalysed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(ii) was evident from the enhanced affinity of CA9-BPS-Cu(ii) towards CD133-positive MDA-MB-231 cells where CA9 is overexpressed vs. CD133-negative cells. Moreover, the efficacy of CA9-BPS-Cu(ii) was successfully demonstrated in a xenograft mouse tumour model.