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Bicyclic imidazolium inhibitors of Gli transcription factor activity

Hom, Marisa E. and Ondrus, Alison E. and Sakata-Kato, Tomoyo and Rack, Paul G. and Chen, James K. (2020) Bicyclic imidazolium inhibitors of Gli transcription factor activity. ChemMedChem, 15 (12). pp. 1044-1049. ISSN 1860-7179. https://resolver.caltech.edu/CaltechAUTHORS:20200409-153209955

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Abstract

Gli transcription factors within the Hedgehog (Hh) signaling pathway direct key events in mammalian development and promote a number of human cancers. Current therapies for Gli‐driven tumors target Smoothened (SMO), a G protein‐coupled receptor‐like protein that functions upstream in the Hh pathway. Although these drugs can have remarkable clinical efficacy, mutations in SMO and downstream Hh pathway components frequently lead to chemoresistance. In principle, therapies that act at the level of Gli proteins, through direct or indirect mechanisms, would be more efficacious. We therefore conducted a screen of 325,120 compounds for their ability to block the constitutive Gli activity induced by loss of Suppressor of Fused (SUFU), a scaffolding protein that directly inhibits Gli function. Our studies reveal a family of bicyclic imidazolium derivatives that can inhibit Gli‐dependent transcription without affecting the ciliary trafficking or proteolytic processing of these transcription factors. We anticipate that these chemical antagonists will be valuable tools for investigating the mechanisms of Gli regulation and developing new strategies for targeting Gli‐driven cancers.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/cmdc.202000169DOIArticle
ORCID:
AuthorORCID
Ondrus, Alison E.0000-0002-6023-3290
Sakata-Kato, Tomoyo0000-0002-8089-5101
Additional Information:© 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. Issue Online: 22 June 2020; Version of Record online: 26 May 2020; Accepted manuscript online: 08 April 2020; Manuscript received: 16 March 2020. Funding Information: NIH. Grant Numbers: R01 GM113100, R35 GM127030. Stanford SPARK.
Funders:
Funding AgencyGrant Number
NIHR01 GM113100
NIHR35 GM127030
Stanford UniversityUNSPECIFIED
Subject Keywords:Hedgehog signaling; Gli; transcription factor; Cancer; Small-Molecule Inhibitor
Issue or Number:12
Record Number:CaltechAUTHORS:20200409-153209955
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200409-153209955
Official Citation:M. E. Hom, A. E. Ondrus, T. Sakata-Kato, P. G. Rack, J. K. Chen. Bicyclic imidazolium inhibitors of Gli transcription factor activity. ChemMedChem 2020, 15, 1044; doi:10.1002/cmdc.202000169
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102470
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:09 Apr 2020 22:54
Last Modified:02 Jul 2020 15:54

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