Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics

Chemical Starting Matter for HNF4α Ligand Discovery and Chemogenomics

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 associa...

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Bibliographic Details
Main Authors: Isabelle Meijer, Sabine Willems, Xiaomin Ni, Jan Heering, Apirat Chaikuad, Daniel Merk
Format: Article
Language:English
Published: MDPI AG 2020-10-01
Series:International Journal of Molecular Sciences
Subjects:
Orphan nuclear receptor
hepatocyte nuclear factor 4α
MODY
type 2 diabetes
fragment-based design
drug discovery
Online Access:https://www.mdpi.com/1422-0067/21/21/7895
Description
Summary: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.
ISSN:1661-6596
1422-0067

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