TY  - JOUR
A1  - Meijer, Isabelle
A1  - Willems, Sabine
A1  - Ni, Xiaomin
A1  - Heering, Jan Peter
A1  - Chaikuad, Apirat
A1  - Merk, Daniel
T1  - Chemical starting matter for HNF4α ligand discovery and chemogenomics
T2  - International Journal of Molecular Sciences
N2  - 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.
KW  - Orphan nuclear receptor
KW  - type 2 diabetes
KW  - fragment-based design
KW  - drug discovery
KW  - MODY
KW  - hepatocyte nuclear factor 4α
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57681
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-576815
SN  - 1422-0067
VL  - 21
IS  - art. 7895
SP  - 1
EP  - 11
PB  - MDPI
CY  - Basel
ER  -