Structural optimization and pharmacokinetics evaluation of glycogen synthase kinase-3β inhibitors as Alzheimer drug candidates

Title: Structural optimization and pharmacokinetics evaluation of glycogen synthase kinase-3β inhibitors as Alzheimer drug candidates

Principal Investigator: Professor Qing. X. Li, PhD

Funded by: Hawaii Community Foundation

Alzheimer’s disease (AD) is the most common form of dementia, causing memory loss and cognitive impairment in conjunction with mental and behavioral changes. AD is the sixth leading cause of death in the U.S. and one-third of seniors die with AD. In 2017, Alzheimer’s cost the U.S. $259 billion. In Hawaii, AD affects 11% of people over the age of 65. Caring for AD family members puts a burden on Hawaii families. In 2016, there were 66,000 dementia caregivers in Hawaii, delivering 75 million hours of unpaid care, at a total value of $944 million. The four AD drugs available on the market only temporarily relieve symptoms. None can prevent, cure or even slow AD.

The cause of AD is unknown. Current knowledge implicates the build-up of tau tangles in the brain is a key problem. Tau tangles are caused by abnormal modification (i.e., phosphorylation) of tau proteins in nerve cells. Glycogen synthase kinase-3β (GSK-3β) is a key enzyme responsible for abnormal phosphorylation of tau proteins. GSK-3β is a promising therapeutic target of AD. No approved drug targets GSK-3b. There is an urgent demand for new GSK-3b-based drugs to treat AD.

We recently discovered that the flavone isoorientin in corn silk selectively inhibit GSK-3β. Our further studies indicated that isoorientin effectively attenuates GSK-3β-mediated tau phosphorylation. In human neuron cells, it was neuroprotective against amyloid-induced neurotoxicity and was nontoxic at an excessively high concentration. Subsequent structural modification of isoorientin led to a novel GSK-3b inhibitor, TFgF-18, that has over 300-fold improved potency and good drug-like properties while retaining high selectivity.

We propose two objectives: (a) design and synthesis of additional potent and selective GSK-3b inhibitors and (b) pharmacokinetic studies of the synthetic GSK-3β inhibitors, including TFgF-18. The purposes are (a) to further optimize the structure of the GSK-3β inhibitors for higher potency, better selectivity and specificity and (b) to assess which drug candidates will be selected for the preclinical studies. The ultimate goal is to develop a drug for AD treatment.

This project is a new line of Hawaii-based medical research to develop GSK-3β inhibitors for AD therapy. It will directly benefit the people of Hawaii. AD patients in Hawaii need an effective drug. Our study will offer new drug candidates with high potency and promising pharmacokinetic properties and will also stimulate the development of nutraceuticals for AD complementary medicine in Hawaii. The new knowledge gained through this study will be a valuable contribution to the field of AD research. The doctoral student and junior researcher trained through this project will be the next generation of local scientists engaging in Alzheimer’s research and drug discovery.