Alzheimer's disease (AD), a progressive neurodegenerative disorder that affects 36 million individuals worldwide is marked by lesions and filaments made up of hyperphosphorylated PHF-tau protein in the hippocampus. Reversing tau phosphorylation is a promising therapeutic strategy to prevent progression of AD. Casein kinase 1 delta (CK1 belongs to the Casein Kinase 1 family comprising of eight isozymes. CK1 is predominantly expressed in the AD hippocampus >30 fold and was found to be co- localized with granulovacuolar degeneration bodies. CK1 plays a critical role in AD through phosphorylation of tau which precedes neuritic lesion formation, strongly implicating CK1in the tau fibrillization reaction pathway. CK1 has been reported to be associated with pathological accumulation of tau in several neurodegenerative diseases including AD, Down syndrome, progressive supranuclear palsy, and Parkinsonism dementia complex of Guam. Inhibition of CK1 has been shown to reduce fibrillar lesions and to inhibit A production. In addition to driving the accumulation of pathogenic tau neurofibrills, CK1 also promotes generation of amyloid-(A ), the causative agent in the development of AD. Our recent work on the investigation of quinones as kinase inhibitors revealed a quinone compound that inhibited CK1 and Pim1 kinase preferentially over CK1 2 and 98 other human protein kinases. Similarity search and preliminary in-vitro CK1 kinase inhibition assay have yielded novel compounds with good potency. This proposal aims to obtain highly selective and potent inhibitors of CK1 by further refining the structure of our active quinones by design and synthesis of new derivatives followed by CK1 inhibition assay. The most promising candidates will then be assessed for their effective inhibition of tau phosphorylation and suppression of A production using multiple pre-clinical models of AD. Our long-term goal is to provide novel and potent CK1 inhibitors which can serve as therapeutic drugs for neurodegenerative disorders such as AD. Our central hypothesis is that the development of new CK1 inhibitors with low nanomolar range inhibition potencies will address the urgent need for therapeutics for the treatment of AD and other neurodegenerative disorders.