Mark Lovell Scope: State Matching: Kentucky Network for Innovation & Commercialization (#KYNETIC#) Yr 5

Currently, Alzheimer’s disease (AD) affects 6.7 million Americans and represents a critical public health issue. Despite considerable investment by multiple pharmaceutical companies there are limited therapeutics available that modify the underlying biology of AD. In fact, the recent FDA approval of two immunotherapeutics (Aduhelm and Leqembi) aimed at reduction of amyloid beta peptide (Aβ) became the first new drugs for AD in the last two decades and the first to directly impact underlying cause of disease. However, Aduhelm and Leqembi are administered IV, are expensive ($26,000 – 30,000/yr) and are limited for use in a narrow segment of AD patients early in disease progression. Therefore, there remains a need for development of additional therapeutics that modulate other aspects of disease pathology that could more readily be prescribed to a broader patient population. In the search for alternative AD therapeutics, the Lovell laboratory developed and characterized a small molecule (UK-5141) with good TAK1 kinase inhibition and aqueous solubility. UK-5141 is not listed in the chemical literature and in silico ADMET predicts it is also brain penetrant in contrast to currently available commercial TAK1 kinase inhibitors. We are currently conducting structure activity relationship assays to identify two lead molecules to be used for further development of an orally available modulator of tau pathology under the KYNETIC program. To accelerate development of an optimal TAK1 kinase inhibitor through the KYNETIC program, we propose to carry out in vitro characterization of two lead molecules (UK-5141-L1 and UK-5141-L2) with the most potent TAK1 kinase inhibition. To ensure our lead molecules are brain penetrant, we also propose to carry out single dose pharmacokinetics and determine brain concentrations in C57/BL6J wildtype mice. To test efficacy of each lead to decrease TAK1 activation and downstream induction of pathologic tau, we will test the molecules in a mouse model of tau pathology. If successful, the proposed studies will identify a final lead molecule for further preclinical testing. The proposed studies combine the strengths of Dr. Lovell who has significant experience in the human and animal model studies of AD and Dr. Prisinzano who has extensive experience in drug design and medicinal chemical optimization.