Design of a Potent TLX Agonist by Rational Fragment Fusion

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.