Page 74 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-40]

Phenotypic discovery of a neuroprotective agent regulating

tau proteostasis in a stress-responsive manner

Young-Hee Shin¹, Hana Cho², Bo Young Choi³, Jonghoon Kim¹, Jaeyoung Ha², Sang Won Suh³, Seung Bum Park¹˙²˙*

¹Chemistry, Seoul National University , Seoul 08826, South Korea, ²Biophysics and Chemical Biology, Seoul

National University , Seoul 08826, South Korea, ³Physiology, College of Medicine, Hallym University, Chuncheon
24252, South Korea

A number of neurodegenerative diseases including tauopathies are caused by an abnormal proteostasis and

accumulation of aggregation-prone proteins in neurons. In order to find small molecules suppressing tau protein

aggregation in cells under endoplasmic reticulum (ER) stress conditions, we performed a phenotype-based screening
using HEK293 Tau BiFC (Bimolecular Fluorescence Complementation)-Venus cells. SB1617 was selected as a leading
compound via a structure activity relationship study for its high potency in reducing tau protein oligomerization

and low cytotoxicity. We obtained a possible target protein list of SB1617 by applying label-free target identification
technology, TS-FITGE (thermal shift Fluorescence difference in two-dimensional gel electrophoresis). Further gene

knockdown experiments for those proteins, biophysical tests and in vitro bio-functional tests revealed that SB1617
activates protein kinase-like endoplasmic reticulum kinase (PERK) signaling under the cell stressed conditions.

Further elucidation of mechanism regarding conditional PERK activation and proteostasis regulation will accelerate
developing therapeutics for neurodegenerative diseases.