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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. PMCID PMC7311267. doi:10.1002/cmdc.202000169.

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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 CentralArticle
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. We gratefully acknowledge support for this work from the NIH (R01 GM113100 and R35 GM127030 to J.K.C.) and Stanford SPARK. We thank Pao-Tien Chuang for the Sufu−/− MEFs; Wade Bushman for the Gli1−/− MEFs; and Sascha Hoogendoorn and Yilin Fan for their help with image analyses of ciliary and cytoplasmic/nuclear Gli distributions, respectively. We also thank Daria Mochly-Rosen and members of her lab for helpful discussions.
Funding AgencyGrant Number
NIHR01 GM113100
NIHR35 GM127030
Stanford UniversityUNSPECIFIED
Subject Keywords:Hedgehog signaling; Gli; transcription factor; Cancer; Small-Molecule Inhibitor
Issue or Number:12
PubMed Central ID:PMC7311267
Record Number:CaltechAUTHORS:20200409-153209955
Persistent URL:
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
Deposited By: Tony Diaz
Deposited On:09 Apr 2020 22:54
Last Modified:15 Feb 2022 18:55

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