Lee, Jae Wook Hirota, Tsuyoshi Kumar, Anupriya Kim, Nam-Jung Irle, Stephan Kay, Steve A. 2024-01-20T06:04:45Z 2024-01-20T06:04:45Z 2021-09-05 2015-09 1860-7179 https://pubs.kist.re.kr/handle/201004/125063 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- 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. English WILEY-V C H VERLAG GMBH DEGRADATION REVEALS FBXL3 Development of Small-Molecule Cryptochrome Stabilizer Derivatives as Modulators of the Circadian Clock Article 10.1002/cmdc.201500260 1 CHEMMEDCHEM, v.10, no.9, pp.1489 - 1497 CHEMMEDCHEM 10 9 1489 1497 scie scopus 000360499400006 2-s2.0-84940371212 Chemistry, Medicinal Pharmacology & Pharmacy Pharmacology & Pharmacy Article DEGRADATION REVEALS FBXL3 3D-QSAR circadian clock cryptochrome protein degradation small molecule