The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex

Jaebong Jang, Sooyoung Chung, Youjeong Choi, Hye Young Lim, Yeongeon Son, Sung Kook Chun, Gi Hoon Son, Kyungjin Kim, Young Ger Suh, Jong Wha Jung

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Aims: We have previously identified a chemical scaffold possessing 2-ethoxypropanoic acid (designated as KS15) that directly binds to the C-terminal region of cryptochromes (CRYs: CRY1 and CRY2) and enhances E-box-mediated transcription. However, it is still unclear how KS15 impairs the feedback actions of the CRYs and which chemical moieties are functionally important for its actions. Main methods: The E-box-mediated transcriptional activities were mainly used to examine the effects of KS15 and its derivatives. Co-immunoprecipitation assays accompanied by immunoblotting were employed to monitor protein-protein associations. We also examined the effects of KS15 and selected derivatives on circadian molecular rhythms in cultured cells. Key findings: The present study shows that KS15 inhibits the interaction between CRYs and Brain-Muscle-Arnt-Like protein 1 (BMAL1), thereby impairing the feedback actions of CRYs on E-box-dependent transcription by CLOCK:BMAL1 heterodimer, an indispensable transcriptional regulator of the mammalian circadian clock. Subsequent structure-activity relationship analyses using a well-designed panel of derivatives identified the structural requirements for the effects of KS15 on CRY-evoked regulation of E-box-mediated transcription. We found that KS15 and several derivatives significantly reduce the amplitude and delayed the phase of molecular circadian rhythms in fibroblast cultures. Significance: Taken together, our results provide valuable information on the molecular mode-of-action as well as the chemical components of the CRYs inhibitor that pharmacologically impact on the transcriptional activity of the CLOCK:BMAL1 heterodimer.

Original languageEnglish
Pages (from-to)49-55
Number of pages7
JournalLife Sciences
StatePublished - 1 May 2018

Bibliographical note

Funding Information:
This work was supported by the Ministry of Science and ICT and the Ministry of Education through the National Research Foundation of Korea ( NRF-2015M3A9E7029176 , NRF-2014R1A6A3A04054863 , NRF-2016M3C7A1904340 and NRF-2017R1D1A1B03032798 ). S. Chung was supported by the Ewha Womans University Research Grant of 2016. We thank Dr. Aziz Sancar at University of North Carolina for providing the Flag/Myc/His-tagged human CRY1 expression construct.

Publisher Copyright:
© 2018 Elsevier Inc.


  • 2-Ethoxypropanoic acid
  • CLOCK:BMAL1 heterodimer
  • Circadian clock
  • Circadian rhythm
  • Cryptochromes (CRYs)
  • KS15


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