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Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement

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 attractive ther...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225008/
https://www.ncbi.nlm.nih.gov/pubmed/34073760
http://dx.doi.org/10.3390/ph14060496
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author 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
author_facet 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
author_sort Jeong, Yong Uk
collection PubMed
description 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 attractive 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 replacement. 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.
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spelling pubmed-82250082021-06-25 Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement 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 Pharmaceuticals (Basel) Article 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 attractive 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 replacement. 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. MDPI 2021-05-24 /pmc/articles/PMC8225008/ /pubmed/34073760 http://dx.doi.org/10.3390/ph14060496 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
title Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
title_full Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
title_fullStr Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
title_full_unstemmed Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
title_short Development of Non-Ethoxypropanoic Acid Type Cryptochrome Inhibitors with Circadian Molecular Clock-Enhancing Activity by Bioisosteric Replacement
title_sort development of non-ethoxypropanoic acid type cryptochrome inhibitors with circadian molecular clock-enhancing activity by bioisosteric replacement
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225008/
https://www.ncbi.nlm.nih.gov/pubmed/34073760
http://dx.doi.org/10.3390/ph14060496
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