Development of Small-Molecule Cryptochrome Stabilizer Derivatives as Modulators of the Circadian Clock

  • ChemMedChem. 2015 Sep;10(9):1489-97. doi: 10.1002/cmdc.201500260.
Jae Wook Lee  1  2 ,  Tsuyoshi Hirota  3  4  5 ,  Anupriya Kumar  6  7 ,  Nam-Jung Kim  1  8 ,  Stephan Irle  9  10 ,  Steve A Kay  11  12
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037 (USA).
  • 2. Natural Product Research Center, Korea Institute of Science and Technology, Department of Biological Chemistry, University of Science and Technology (Republic of Korea).
  • 3. Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, 464-8601 (Japan). [email protected].
  • 4. Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA, 90089 (USA). [email protected].
  • 5. PRESTO, Japan Science and Technology Agency, Nagoya, 464-8601 (Japan). [email protected].
  • 6. Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, 464-8601 (Japan). [email protected].
  • 7. Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya, 464-8602 (Japan). [email protected].
  • 8. Collage of Pharmacy, Kyung Hee University, Seoul, 130-701 (Republic of Korea).
  • 9. Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, 464-8601 (Japan).
  • 10. Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya, 464-8602 (Japan).
  • 11. Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, 464-8601 (Japan). [email protected].
  • 12. Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA, 90089 (USA). [email protected].
PMID: 26174033 DOI: 10.1002/cmdc.201500260
Abstract

Small-molecule probes have been playing prominent roles in furthering our understanding of the molecular underpinnings of the circadian clock. We previously discovered a carbazole derivative, KL001 (N-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-N-(furan-2-ylmethyl)methanesulfonamide), as a stabilizer of the clock protein Cryptochrome (CRY). Herein we describe an extensive structure-activity relationship analysis of KL001 derivatives leading to the development of a highly active derivative: 2-(9H-carbazol-9-yl)-N-(2-chloro-6-cyanophenyl)acetamide (KL044). Subsequent 3D-QSAR analysis identified critical features of KL001 derivatives and provided a molecular-level understanding of their interaction with CRY. The electron-rich carbazole, amide/hydroxy linker, sulfonyl group, and electron-withdrawing nitrile moieties contribute to greater biological activity. The hydrogen bonding interactions with Ser394 and His357 as well as stronger CH-π interactions with Trp290 make KL044 a better binder than KL001. KL044 lengthened the circadian period, repressed Per2 activity, and stabilized CRY in reporter assays with roughly tenfold higher potency than KL001. Altogether, KL044 is a powerful chemical tool to control the function of the circadian clock through its action on CRY.

Keywords
3D-QSAR; circadian clock; cryptochrome; protein degradation; small molecule.
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