Development of non-ethoxypropanoic acid type cryptochrome inhibitors with circadian molecular clock-enhancing activity by bioisosteric replacement

Yong Uk Jeong, Hyo Eon Jin, Hye Young Lim, Goyeong Choi, Hansol Joo, Bohun Kang, Ga Hyun Lee, Kwang Hyeon Liu, Han Joo Maeng, Sooyoung Chung, Gi Hoon Son, Jong Wha Jung

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Circadian dysfunction is closely associated with an increased risk of various diseases. Considering that molecular clock machinery serves as an intrinsic time-keeping system underlying the circadian rhythm of biological processes, the modulation of the molecular clock machinery is an at-tractive therapeutic target with novel mechanisms of action. Based on the previous structure–activity relationship study of small molecule cryptochrome (CRY) inhibitors possessing an ethoxypropanoic acid moiety, non-ethoxypropanoic acid-type inhibitors have been developed by bioisosteric replace-ment. They were evaluated as potent and effective enhancers of E-box-mediated transcription, and, in particular, ester 5d and its hydrolysis product 2d exhibited desirable metabolic and pharmacokinetic profiles as promising drug candidates. Compound 2d directly bound to both CRY1 and 2 in surface plasmon resonance analyses, suggesting that the molecular target is CRY. Effects of compound 5d and 2d on suppressive action of CRY1 on CLOCK:BMAL1-activated E-box-LUC reporter activity revealed that both compounds inhibited the negative feedback actions of CRY on CLOCK:BMAL1. Most importantly, compounds 5d and 2d exhibited significant effects on molecular circadian rhythmicity to be considered circadian clock-enhancers, distinct from the previously developed CRY inhibitors possessing an ethoxypropanoic acid moiety.

Original languageEnglish
Article number496
Issue number6
Publication statusPublished - 2021

Bibliographical note

Funding Information:
Funding: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (Grant No. 2015M3A9E7029176, 2019M3C7A1032764, 2020R1C1C1013670 and 2020R1A5A2017323) and the 4th BK21 project funded by the Korean Ministry of Education (5199990614732). G.H.S was supported by the Korea University Research Grant.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Bioisosteric replacement
  • Circadian clock
  • Circadian rhythm
  • Cryptochrome inhibitor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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