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 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.
Author:Isabelle Meijer, Sabine Willems, Xiaomin NiORCiDGND, Jan Peter HeeringORCiDGND, Apirat ChaikuadORCiD, Daniel MerkORCiDGND
Parent Title (English):International Journal of Molecular Sciences
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/10/24
Date of first Publication:2020/10/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/02/10
Tag:MODY; Orphan nuclear receptor; drug discovery; fragment-based design; hepatocyte nuclear factor 4α; type 2 diabetes
Issue:art. 7895
Page Number:11
First Page:1
Last Page:11
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0