121st General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code MEDI.P-614
Subject KDS4070, A Novel Nrf2 activator as a Neuroprotective Agent for Treatment of Parkinson’s disease
Authors SU JEONG SHIN, Ki Duk Park*
Convergence Research Center for DTC, Korea Institute of Science and Technology, Korea
Abstract In recent years, several studies have suggested that oxidative stress and neuroinflammation play a critical roles in the pathogenesis of neurodegenerative diseases, including Parkinson disease (PD) which is characterized by abnormalities in motor control and muscle rigidity. Especially, oxidative stress causes the striatal dopamine (DA) deficiency by neuronal loss in the substantia nigra (SN). We have focused on the fact that nuclear factor-E2-related factor-2 (Nrf2) signaling is a key pathway for cellular defense systems against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of various antioxidant enzyme genes. We have previously synthesized and reported novel vinyl sulfone derivative (KDS4048) as Nrf2 activator. Here, we changed vinyl sulfone group in KDS4048 with either vinyl sulfone amine or vinyl sulfonate. We observed that the effect of the vinyl sulfone amine derivative (KDS4069) on Nrf2 activation was greatly reduced (KDS4069 EC50 = 6.35 μM). Interestingly, the vinyl sulfonate derivative (KDS4070) exhibited remarkably excellent effect on Nrf2 activation (KDS4048 EC50 = 0.530 μM vs KDS4070 EC50 = 0.076 μM). The new Nrf2 activator, KDS4070, was confirmed to induce expression of the Nrf2 dependent antioxidant enzymes such as GCLM and HO-1 at protein levels in microglial BV-2 cells. In addition, KDS4070 protected DAergic neurons and consequently attenuated PD-associated behavioral deficits in the MPTP-induced mouse model of PD. We are conducting additional experiments to evaluate in vitro & in vivo efficacy of KDS4070.
E-mail 216505@kist.re.kr