Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics.
MODY
Orphan nuclear receptor
drug discovery
fragment-based design
hepatocyte nuclear factor 4α
type 2 diabetes
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
24 Oct 2020
24 Oct 2020
Historique:
received:
14
09
2020
revised:
16
10
2020
accepted:
21
10
2020
entrez:
29
10
2020
pubmed:
30
10
2020
medline:
3
3
2021
Statut:
epublish
Résumé
Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure-activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range. These compounds demonstrate the druggability of HNF4α and thus provide a starting point for medicinal chemistry as well as an early tool for chemogenomics.
Identifiants
pubmed: 33114319
pii: ijms21217895
doi: 10.3390/ijms21217895
pmc: PMC7660650
pii:
doi:
Substances chimiques
HNF4A protein, human
0
Hepatocyte Nuclear Factor 4
0
Ligands
0
Small Molecule Libraries
0
FBP1 protein, human
EC 3.1.3.11
Fructose-Bisphosphatase
EC 3.1.3.11
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
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