Design of a Potent TLX Agonist by Rational Fragment Fusion

  • J Med Chem. 2022 Feb 10;65(3):2288-2296. doi: 10.1021/acs.jmedchem.1c01757.
Giuseppe Faudone  1 ,  Rezart Zhubi  1  2 ,  Fatih Celik  1 ,  Stefan Knapp  1  2 ,  Apirat Chaikuad  1  2 ,  Jan Heering  3 ,  Daniel Merk  1  4
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, D-60438 Frankfurt, Germany.
  • 2. Structural Genomics Consortium, BMLS, Goethe University Frankfurt, D-60438 Frankfurt, Germany.
  • 3. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, D-60596 Frankfurt, Germany.
  • 4. Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.
PMID: 34989568 DOI: 10.1021/acs.jmedchem.1c01757
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.

Products