TFEB Activator for Alzheimer's Disease Therapy

One in ten of the persons ageare affected by Alzheimer s diseaseADcausing enormous social and
economic burden to the United StatesTo date only five medications have been approved by the FDA for the
treatment of the symptoms of ADbut none of them slows or stops the disease progressionWith the recent
repeated failures of AD drugs on thesecretase inhibitorsthe need for an effective AD drug became even
more pressing and it also prompted the development of the new drugs on alternative mechanisms of actionsAccumulating evidence suggests that autophagy lysosome pathwayALPassociated defects play a crucial
role in AD pathogenesis and this pathway is considered a potential target for the development of AD drugsRecentlytranscription factor TFEB was found to increase biogenesis of new lysosomes and the entire ALP by
activating more thangenesTFEB overexpression resulted in marked reduction of both PHF tau and
amyloid plaque burden in mouse models of ADAdditionallyTFEB has also demonstrated efficacy in clearing
protein aggregates in models of Parkinson s and Huntington s diseasesMoreoverTFEB stimulates both
endocytosis and exocytosiswhich additionally enhances cellular clearanceThuswe hypothesize that TFEB
activation may be a promising mechanism to effectively modify AD progression and TFEB activators may be
developed into disease modifying drugs for ADAiming to develop TEFB activators into disease modifying drugs for ADin a joint research project between
Brilliant BioSciences Inc and Torrey Pines Institute for Molecular Studieswe have identified a small molecule
hit exhibiting potent TFEB activation and producing efficacy in reducing Alevels in cell linesThe hit passed
through the blood brain barrier in miceand had a therapeutic window ofin rat primary cortical neurons
and AD fibroblastsThese data suggest that the hit may be promising for the development of the disease
modifying drug for ADHoweverthe hit is quite hydrophobic with a cLogP value beyond therangeThereforein the STTR phase I study we will conduct medicinal chemistry to optimize the hit to increase its
hydrophilicity while improving maintaining the activity toward TFEBWe will also test the analogs for their
biological activities such as dephosphorylation of TFEB and nuclear translocation of EGFP TFEB in AD
fibroblastsand examine their toxicity in both primary neurons and fibroblasts derived from AD patientsThe
best compound will then be tested for the effect on neurofibrillary tangle pathology and amyloid plaque burden
using SAMPmice as a model of ADBy the end of the project periodthe goal is to obtain one or more compounds that have a cLogP in the
range ofactivates TFEB dephosphorylation and nuclear translocation in AD fibrolasts at a concentration ofnMand produces clearance of plaque or tangle burden in the SAMPmouse model of ADWe will carry
this lead forward to the Phase II study for further development of the disease modifying drugs for AD PROJECT NARRATIVE
As available treatments for Alzheimer s disease only provide temporary symptomatic relief without slowing and
stopping the disease progressand the clinical trials repeated failed on AD drugs based on inhibition ofsecretaseand anti amyloidspecific monoclonal antibodieswe hypothesize TFEB activation as an
alternative mechanism to develop AD therapyA promising small molecule hit has been identified that showed
potential in increasing house keeping function and clearing cellular debris in cells by activation of TFEB dephosphorylation and nuclear translocationWe will pursue medicinal chemistry modification of the hit to
validate the feasibility of our hypothesis in this Phase I research