p21 Inducers as Neuroprotective and Anticancer Agents

This invention discloses small molecules that activate the p21CIP1/WAF1, a protein that is not only neuroprotective, but promotes neurite remodeling and axonal regeneration. The most effective compounds in the screen included ciclopirox, dihydrocelastrol, chloroquine, colistimethate sodium, lycorine, acacetin, diphenylurea, and acetylcysteine.

These compounds have been further tested in primary neurons in vitro, and ciclopirox has been tested in a mouse model of spinal cord injury.

This work arose as part of a larger project led by Dr. Raj Ratan, which has screened drugs and drug-like compounds in high throughput screens relevant to the program of destruction, cell-suicide, and scarring that characterize damage to the CNS, including stroke, traumatic brain injury, and spinal cord injury. The project has sought compounds that have activity against multiple targets -- or against a single target that can set off wide-ranging protective programs.

The general approach is described in a recent piece in Stroke called "Novel multi-modal strategies to promote brain and spinal cord injury recovery".

The primary screens have sought:

• HIF activators / prolyl hydroxylase inhibitors (2009 J Neurosci; 2008 Ann N Y Acad Sci; 2008 Front. Bioscience ; 2007 Neurochem Res; 2004 Stroke);
• Arginase 1 activators (2010 J Neurosci; 2006 J Neurosci; 2004 J Nutrition)
• p21CIP1/WAF1 activators (2008 J Neurosci)
• ATF4 inhibitors (2008 J Exp Med)