PMID- 32268014
OWN - NLM
STAT- MEDLINE
DCOM- 20210614
LR  - 20210618
IS  - 1860-7187 (Electronic)
IS  - 1860-7179 (Print)
IS  - 1860-7179 (Linking)
VI  - 15
IP  - 12
DP  - 2020 Jun 17
TI  - Bicyclic Imidazolium Inhibitors of Gli Transcription Factor Activity.
PG  - 1044-1049
LID - 10.1002/cmdc.202000169 [doi]
AB  - 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 screened 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.
CI  - (c) 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
FAU - Hom, Marisa E
AU  - Hom ME
AD  - Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., 
      CCSR 3155, Stanford, CA 94305, USA.
FAU - Ondrus, Alison E
AU  - Ondrus AE
AD  - Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., 
      CCSR 3155, Stanford, CA 94305, USA.
AD  - Present address: Division of Chemistry and Chemical Engineering, California 
      Institute of Technology, Pasadena, CA 91125, USA.
FAU - Sakata-Kato, Tomoyo
AU  - Sakata-Kato T
AD  - Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., 
      CCSR 3155, Stanford, CA 94305, USA.
AD  - Present address: Global Health Drug Discovery Institute, Beijing, 100192, China.
FAU - Rack, Paul G
AU  - Rack PG
AD  - Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., 
      CCSR 3155, Stanford, CA 94305, USA.
AD  - Present address: Thermo Fisher Scientific, Carlsbad, CA 92008, USA.
FAU - Chen, James K
AU  - Chen JK
AUID- ORCID: 0000-0002-9220-8436
AD  - Department of Chemical and Systems Biology, Stanford University, 269 Campus Dr., 
      CCSR 3155, Stanford, CA 94305, USA.
AD  - Department of Developmental Biology, Stanford University, 269 Campus Dr., CCSR 
      3155, Stanford, CA 94305, USA.
AD  - Department of Chemistry, Stanford University, 269 Campus Dr., CCSR 3155, 
      Stanford, CA 94305, USA.
LA  - eng
GR  - R01 GM113100/GM/NIGMS NIH HHS/United States
GR  - R35 GM127030/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200526
PL  - Germany
TA  - ChemMedChem
JT  - ChemMedChem
JID - 101259013
RN  - 0 (Gli1 protein, mouse)
RN  - 0 (Heterocyclic Compounds, 2-Ring)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (Imidazoles)
RN  - 0 (Zinc Finger Protein GLI1)
SB  - IM
MH  - Animals
MH  - Heterocyclic Compounds, 2-Ring/chemical synthesis/pharmacology
MH  - Heterocyclic Compounds, 3-Ring/chemical synthesis/pharmacology
MH  - Imidazoles/chemical synthesis/*pharmacology
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mice
MH  - Mitochondria/drug effects
MH  - Molecular Structure
MH  - NIH 3T3 Cells
MH  - Oxidative Phosphorylation/drug effects
MH  - Signal Transduction/drug effects
MH  - Structure-Activity Relationship
MH  - Zinc Finger Protein GLI1/*antagonists & inhibitors
PMC - PMC7311267
MID - NIHMS1584089
OTO - NOTNLM
OT  - Gli
OT  - Hedgehog signaling
OT  - cancer
OT  - small-molecule inhibitor
OT  - transcription factor
COIS- Conflict of Interest The authors declare no conflict of interest.
EDAT- 2020/04/09 06:00
MHDA- 2021/06/16 06:00
PMCR- 2021/06/17
CRDT- 2020/04/09 06:00
PHST- 2020/03/16 00:00 [received]
PHST- 2020/04/09 06:00 [pubmed]
PHST- 2021/06/16 06:00 [medline]
PHST- 2020/04/09 06:00 [entrez]
PHST- 2021/06/17 00:00 [pmc-release]
AID - 10.1002/cmdc.202000169 [doi]
PST - ppublish
SO  - ChemMedChem. 2020 Jun 17;15(12):1044-1049. doi: 10.1002/cmdc.202000169. Epub 2020 
      May 26.