Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.

Comments:

It sounds like you're summarizing a research study or article related to the DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases and their involvement in neurodegenerative diseases, specifically Alzheimer's disease (AD) and Down syndrome. The study discusses DYRK1A protein kinase as a potential therapeutic target for AD and explores the inhibitory activities of a new class of dihydroquinolines on both DYRK1A and CLK1 (CDC2-like kinases) in the nanomolar range. These inhibitors, including the most potent one named 1p, have shown antioxidant and radical scavenging properties, suggesting a potential dual benefit in targeting both kinase activity and oxidative stress, which is known to be involved in AD. Additionally, the study discusses drug-likeness and molecular docking studies of these inhibitors.

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