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Design of a Potent TLX Agonist by Rational Fragment Fusion.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 2288-2296. Date of Electronic Publication: 2022 Jan 06. - Publication Year :
- 2022
-
Abstract
- As a master regulator of neurogenesis, the orphan nuclear receptor tailless homologue (TLX, NR2E1) maintains neuronal stem cell homeostasis by acting as a transcriptional repressor of tumor suppressor genes. It is hence considered as an appealing target for the treatment of neurodegenerative diseases, but a lack of potent TLX modulators as tools to probe pharmacological TLX control hinders further validation of its promising potential. Here, we report the development of a potent TLX agonist based on fragment screening, pharmacophore modeling, and fragment fusion. Pharmacophore similarity of a fragment screening hit and the TLX ligand ccrp2 provided a rational basis for fragment linkage, which resulted in several TLX activator scaffolds. Among them, the fused compound 10 evolved as a valuable TLX agonist tool with submicromolar potency and high selectivity over related nuclear receptors, rendering it suitable for functional studies on TLX.
- Subjects :
- Animals
Cell Survival drug effects
Drug Stability
HEK293 Cells
Humans
Ligands
Microsomes, Liver metabolism
Orphan Nuclear Receptors metabolism
Piperazine chemistry
Piperazine metabolism
Piperazine pharmacology
Protein Binding
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Drug Design
Orphan Nuclear Receptors agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34989568
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01757