8-Hydroxyquinoline derivatives suppress GLI1-mediated transcription through multiple mechanisms.

Autor: Wen J; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Charan Dash R; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Zaino AM; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Harrahill NJ; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Calhoun JT; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Dusek CO; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Morel SR; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Russolillo M; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States., Kyle Hadden M; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Rd, Unit 3092, Storrs, CT 06029-3092, United States. Electronic address: kyle.hadden@uconn.edu.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Mar; Vol. 132, pp. 106387. Date of Electronic Publication: 2023 Jan 21.
DOI: 10.1016/j.bioorg.2023.106387
Abstrakt: Aberrant activation of the Hedgehog (Hh) signaling pathway has been observed in various human malignancies. Glioma-associated oncogene transcription factor 1 (GLI1) is the ultimate effector of the canonical Hh pathway and has also been identified as a common regulator of several tumorigenic pathways prevalent in Hh-independent cancers. The anti-cancer potential of GLI1 antagonism with small molecule inhibitors has demonstrated initial promise; however, the continued development of GLI1 inhibitors is still needed. We previously identified a scaffold containing an 8-hydroxyquinoline as a promising lead GLI1 inhibitor (compound 1). To further develop this scaffold, we performed a systematic structure-activity relationship study to map the structural requirements of GLI1 inhibition by this chemotype. A series of biophysical and cellular experiments identified compound 39 as an enhanced GLI1 inhibitor with improved activity. In addition, our studies on this scaffold suggest a potential role for SRC family kinases in regulating oncogenic GLI1 transcriptional activity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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