Phase I STTR: Targeting substrate of gamma-secretase for selective amyloid reduction in Alzheimer’s Disease

Amyloid plaque is a pathological hallmark of Alzheimer’s disease (AD). The inhibition of g-secretase to reduce amyloid load has been a prominent strategy in AD drug discovery, but clinical trials of g-secretase inhibitors failed due to side effects and worsening memory deficits in patients. In an effort to circumvent these problems, we will carry out drug discovery that targets the transmembrane domain of the amyloid precursor protein (APPTM), which is the substrate of g-secretase. The long-term goal is to create drugs that selectively reduce amyloid production for disease-modifying treatment of AD. In this proposal, we will first carry out SAR of C1 and lead optimization based on both drug activity and in cellulo ADME(aim 1); then we will carry out In vivo PK and PD studies to characterize pre-clinical candidates (aim 2).