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Reinventing drug discovery
Date:4/19/2013

lab began by first studying the disease in mice, growing billions of motor neurons from mouse embryonic stem cells, half normal and half with a genetic mutation known to cause ALS.

Investigators starved the cells of nutrients and then screened five thousand drug-like molecules to find any that would keep the motor neurons alive.

Several hits were identified, but the molecule that best prolonged the life of both normal and ALS motor neurons was kenpaullone, previously known for blocking the action of an enzyme (GSK-3) that switches on and off several cellular processes, including cell growth and death. "Shockingly, this molecule keeps cells alive better than the standard culture medium that everybody keeps motor neurons in," Rubin said.

Kenpaullone proved effective in several follow-up experiments that put mouse motor neurons in situations of certain death. Neuron survival increased in the presence of the molecule whether the cells were programmed to die or placed in a toxic environment.

After further investigation, Rubin's lab discovered kenpaullone's potency comes from its ability to also inhibit HGK an enzyme that sets off a chain of reactions that leads to motor neuron death. This enzyme was not previously known to be important in motor neurons or associated with ALS, marking the discovery of a new drug target for the disease.

"I think that stem-cell screens will discover new compounds that have never been discovered before by other methods," Rubin said. "I'm excited to think that someday one of them might actually be good enough to go into the clinic."

To find out if kenpaullone works in diseased human cells, Rubin's lab exposed patient motor neurons and motor neurons grown from human embryonic stem cells to the molecule, as well as two drugs that did well in mice but failed in phase III human clinical trials for ALS. Once again, kenpaullone increased the rate of neuron survival, while one drug saw little
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Contact: B. D. Colen
bd_colen@harvard.edu
617-413-1224
Harvard University
Source:Eurekalert

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