An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals.

Simon Miller, Yoshiki Aikawa, Akiko Sugiyama, Yoshiko Nagai, Aya Hara, Tsuyoshi Oshima, Kazuma Amaike, Steve A Kay, Kenichiro Itami, Tsuyoshi Hirota

Cell chemical biology 2020 Sep 17

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Cryptochrome 1 (CRY1) and CRY2 are core regulators of the circadian clock, and the development of isoform-selective modulators is important for the elucidation of their redundant and distinct functions. Here, we report the identification and functional characterization of a small-molecule modulator of the mammalian circadian clock that selectively controls CRY1. Cell-based circadian chemical screening identified a thienopyrimidine derivative KL201 that lengthened the period of circadian rhythms in cells and tissues. Functional assays revealed stabilization of CRY1 but not CRY2 by KL201. A structure-activity relationship study of KL201 derivatives in combination with X-ray crystallography of the CRY1-KL201 complex uncovered critical sites and interactions required for CRY1 regulation. KL201 bound to CRY1 in overlap with FBXL3, a subunit of ubiquitin ligase complex, and the effect of KL201 was blunted by knockdown of FBXL3. KL201 will facilitate isoform-selective regulation of CRY1 to accelerate chronobiology research and therapeutics against clock-related diseases. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Simon Miller, Yoshiki Aikawa, Akiko Sugiyama, Yoshiko Nagai, Aya Hara, Tsuyoshi Oshima, Kazuma Amaike, Steve A Kay, Kenichiro Itami, Tsuyoshi Hirota. An Isoform-Selective Modulator of Cryptochrome 1 Regulates Circadian Rhythms in Mammals. Cell chemical biology. 2020 Sep 17;27(9):1192-1198.e5