Summary: A preclinical drug that inhibits the kinase enzyme Cdk5 may have the potential to treat depression, brain injuries, and disorders associated with cognitive impairment.

The drug, which notably is brain-permeable, acts to inhibit the kinase enzyme Cdk5.

While inhibitors of Cdk5 could offer potential therapeutic benefits and new ways to study basic brain function, previous first- and second-generation anti-Cdk5 compounds largely get blocked at the blood-brain barrier that restricts movement of solutes from the blood to the central nervous system’s extracellular fluid.

They also show that systemic administration of 25-106 alters neurobehavior in mice, reducing anxiety-like behavior.

“As perhaps the first robust systemic inhibitor, 25-106 represents an exciting and expandable and translatable pharmacological tool to study the function of Cdk5 activity in wild-type animals,” said Bibb, a professor in the University of Alabama at Birmingham Department of Surgery.

“Achieving systemic applicability may be considered a step forward toward the testing of Cdk5 inhibitors to treat neuropsychiatric and neurodegenerative diseases.

The study, “Systemic administration of a brain permeable Cdk5 inhibitor alters neurobehavior,” is published in the journal Frontiers in Pharmacology.

They showed that 25-106 inhibited Cdk5 activity in a dose-dependent manner in brain striatal slices ex vivo, and that it also penetrated the brain after systemic administration in mice to inhibit Cdk5 in vivo.

They found that 25-106 is a non-selective inhibitor of both Cdk5 and another cyclin-dependent kinase, Cdk2, but note that very low levels of Cdk2 are found in the brain.

“Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior” by Alan Umfress et al.

Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior.

While intracranial infusions or treatment of acutely dissected brain tissue with compounds that inhibit Cdk5 have allowed the study of kinase function and corroborated conditional knockout findings, potent brain-penetrant systemically deliverable Cdk5 inhibitors are extremely limited, and no Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative diseases to date

Here, we screened aminopyrazole-based analogs as potential Cdk5 inhibitors and identified a novel analog, 25–106, as a uniquely brain-penetrant anti-Cdk5 drug

Altogether, 25–106 represents a promising preclinical Cdk5 inhibitor that can be systemically administered with significant potential as a neurological/neuropsychiatric therapeutic