Prexasertib’s Protective Effects Seen in Models of Neurodegeneration

Prexasertib, a small molecule inhibitor that’s been tested in clinical trials for cancer, may represent a new strategy for treating multiple sclerosis (MS) and other neurodegenerative conditions, a study found.

The compound, which inhibits the checkpoint kinase (Chk2) protein, was found to promote nerve cell survival and regeneration after damage, resulting in significant improvements in vision in an animal model of optic neuritis, and in sensory and motor functions in another model of spinal cord injury.

“This study raises the possibility of a completely new treatment strategy for a variety of neurodegenerative diseases, that is aimed at supporting nervous system function and slowing the progression of disease,” Richard Tuxworth, PhD, study senior author and a professor at the University of Birmingham’s Institute of Cancer and Genomic Sciences, said in a university press release.

The study, “Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury,” was published in Science Advances.

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In MS and many other neurological conditions, a type of DNA damage called double-stranded breaks is common in nerve cells. If it’s not fully repaired, the DNA damage response system is chronically activated in cells, contributing to neuronal dysfunction and cellular death.

The repair of double-stranded breaks in DNA often involves activating the checkpoint kinase-2 (Chk2) or Chk1 proteins. These proteins are master regulators of the repair system and blocking them could prevent the chronic activation of the DNA damage response and restore neuronal health.

Researchers from the University of Birmingham, the U.K., and Shaqra University, Saudi Arabia, found targeting the Chk2 pathway could be neuroprotective in multiple animal models of disease.

“Our research started out exploring DNA damage pathways activated following nerve injury. However, the same molecular factors feature in pathways are seen in neurodegenerative diseases, and a full understanding of these mechanisms is an important step towards identifying potential targets for drug treatments,” Zubair Ahmed, PhD, lead study author and a professor of neuroscience at the Institute of Inflammation and Ageing, said.

The research team first used genetic engineering techniques to reduce Chk2 and Chk1 production in a fruit fly model of amyloid toxicity, wherein clumps of the amyloid protein cause damage to nerve cells. Results showed blocking Chk2 production, but not Chk1, could protect neurons and extend survival.

Next, the researchers used rat dorsal root ganglion neurons (DRGNs) cultured in the lab and treated to mimic spinal cord injury. Experiments showed that inhibiting Chk2, but not Chk1, activation promoted nerve cell survival and regeneration, again highlighting “Chk2 as the key target molecule.”

Researchers then turned to rat models of spinal cord injury and optic neuritis, a form of inflammation in the optic nerve common in people with multiple sclerosis. Both models were treated with Eli Lilly‘s investigational Chk2 inhibitor prexasertib.

Results showed significant neuronal regeneration and neurite outgrowth (a measure of neuronal health) in treated animals. The inhibitor also improved sensory and walking function in the rats with spinal cord injury and restored vision in the animals with optic neuritis.

“This study shows that Chk2 inhibitors, including the repurposing candidate prexasertib, promote neuroprotection, axon regeneration, and marked restoration of lost function after [central nervous system] injury,” the researchers wrote. “Inhibition of Chk2 is an exciting and clinically feasible new approach with potential to address the unmet clinical needs of patients with acute neurotrauma.”