Benzobisthiazoles Represent a Novel Scaffold for Kinase Inhibitors of CLK Family Members

Protein kinases are essential regulators
of most cellular processes
and are involved in the etiology and progression of multiple diseases.
The cdc2-like kinases (CLKs) have been linked to various neurodegenerative
disorders, metabolic regulation, and virus infection, and the kinases
have been recognized as potential drug targets. Here, we have developed
a screening workflow for the identification of potent CLK2 inhibitors
and identified compounds with a novel chemical scaffold structure,
the benzobisthiazoles, that has not been previously reported for kinase
inhibitors. We propose models for binding of these compounds to CLK
family proteins and key residues in CLK2 that are important for the
compound interactions and the kinase activity. We identified structural
elements within the benzobisthiazole that determine CLK2 and CLK3
inhibition, thus providing a rationale for selectivity assays. In
summary, our results will inform structure-based design of CLK family
inhibitors based on the novel benzobisthiazole scaffold.