Design of a Potent TLX Agonist by Rational Fragment Fusion

Faudone, Giuseppe; Zhubi, Rezart; Celik, Fatih; Knapp, Stefan; Chaikuad, Apirat; Heering, Jan und Merk, Daniel (2022): Design of a Potent TLX Agonist by Rational Fragment Fusion. In: Journal of Medicinal Chemistry, Vol. 65, No. 3: pp. 2288-2296

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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Pharmacy
• Subjects: 500 Science > 540 Chemistry
• ISSN: 0022-2623
• Language: English