Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
- Authors
- Jeong, Yong Uk; Jin, Hyo-Eon; Lim, Hye Young; Choi, Goyeong; Joo, Hansol; Kang, Bohun; Lee, Ga-Hyun; Liu, Kwang-Hyeon; Maeng, Han-Joo; Chung, Sooyoung; Son, Gi Hoon; Jung, Jong-Wha
- Issue Date
- Jun-2021
- Publisher
- MDPI
- Keywords
- Bioisosteric replacement; Circadian clock; Circadian rhythm; Cryptochrome inhibitor
- Citation
- Pharmaceuticals, v.14, no.6
- Journal Title
- Pharmaceuticals
- Volume
- 14
- Number
- 6
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/81606
- DOI
- 10.3390/ph14060496
- ISSN
- 1424-8247
- Abstract
- 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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