2. Academic Validation
  3. Discovery of new ERRγ agonists regulating dopaminergic neuronal phenotype in SH-SY5Y cells

Discovery of new ERRγ agonists regulating dopaminergic neuronal phenotype in SH-SY5Y cells

  • Bioorg Chem. 2022 May;122:105716. doi: 10.1016/j.bioorg.2022.105716.
Taewoo Kim 1,  Hyo In Kim 1,  Haejun Oh 1,  Yoonsu Jeon 1,  Hyeyoung Shin 1,  Hyun Su Kim 1,  Juhee Lim 2,  Changjin Lim 3,  Jakyung Yoo 4,  Young-Ger Suh 1,  Woo Sung Son 1,  Hyun Jin Choi 5,  Seok-Ho Kim 6
Affiliations

Affiliations

  • 1 College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, 120 Haeryong-ro, Pocheon-si, Gyeonggi-do 11160, Republic of Korea.
  • 2 College of Pharmacy, Woosuk University, Wanju-gun 55338, Republic of Korea.
  • 3 School of Pharmacy, Jeonbuk National University, Jeonju 54896, Republic of Korea.
  • 4 D5 Therapeutics, A703, Hyundai-JisikSanEop Center, 3 Godeung-ro, Sujeong-gu, Seongnam-si, Gyeonggi-do 13105, Republic of Korea.
  • 5 College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, 120 Haeryong-ro, Pocheon-si, Gyeonggi-do 11160, Republic of Korea. Electronic address: hjchoi3@cha.ac.kr.
  • 6 College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, 120 Haeryong-ro, Pocheon-si, Gyeonggi-do 11160, Republic of Korea. Electronic address: ksh3410@cha.ac.kr.
PMID: 35303621 DOI: 10.1016/j.bioorg.2022.105716
Abstract

The discovery of small molecules that regulate specific neuronal phenotypes is important for the development of new therapeutic candidates for neurological diseases. Estrogen-related receptor γ (ERRγ), an orphan nuclear receptor widely expressed in the central nervous system (CNS), is closely related to the regulation of neuronal metabolism and differentiation. We previously reported that upregulation of ERRγ could enhance dopaminergic neuronal phenotypes in the neuroblastoma cell line, SH-SY5Y. In this study, we designed and synthesized a series of new ERRγ agonists using the X-ray crystal structure of the GSK4716-bound ERRγ complex and known synthetic ligands. Our new ERRγ agonists exhibited increased transcriptional activities of ERRγ. In addition, our molecular docking results supported the experimental findings for ERRγ agonistic activity of the potent analogue, 5d. Importantly, 5d not only enhanced the expression of dopaminergic neuronal-specific molecules, TH and DAT but also activated the relevant signaling events, such as the CREB-mediated signaling pathway. The results of the present study may provide useful clues for the development of novel ERRγ agonists for neurological diseases related to the dopaminergic nervous system.

Keywords

CREB; DAT; DY131; Dopaminergic (DAergic) phenotypes; ERRγ agonist; GSK4716; Neurodegenerative diseases; TH.

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