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Some compounds such as paclitaxel and epothilone D are known to kill cancer cells by stabilizing those cells’ microtubules, thereby blocking cell division so that the cancer cells die. Stabilizing microtubules also turns out to be important in fighting neurodegenerative diseases, such as Alzheimer’s disease. That’s because tau proteins ordinarily stabilize the microtubule networks that act as a highway for axons in nerve cells. In certain neurodegenerative diseases such as Alzheimer’s, however, tau proteins become misfolded and lose their ability to stabilize the microtubule networks. Ultimately, nerve signal transmission is lost. Scientists have looked at microtubule-stabilizing compounds as potential therapies for neurodegenerative diseases, but so far they’ve found few small molecules that can be administered orally and also cross the blood-brain barrier. Now, researchers at the University of Pennsylvania’s Center for Neurodegenerative Disease Research in collaboration with the school’s chemistry department report several microtubule-stabilizing small molecules that have promising pharmacokinetic properties (J. Med. Chem. 2014, DOI: 10.1021/jm5005623). Certain triazolopyrimidines (example shown) and phenylpyrimidines are orally bioavailable and able to penetrate the brain. They appear to stabilize microtubules in mouse brains, making them promising leads for treating neurodegenerative disease, the researchers note.
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