Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 3, Pages 2288-2296Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01757
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Funding
- Aventis Foundation (Life Science Bridge Award)
- AbbVie
- Bayer AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genentech
- Genome Canada [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond
- Innovative Medicines Initiative 2 Joint Undertaking [875510]
- Janssen
- Merck KGaA
- Merck Co
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
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TLX is a master regulator of neurogenesis and acts as a transcriptional repressor of tumor suppressor genes to maintain neuronal stem cell homeostasis. The development of a potent TLX agonist, with submicromolar potency and high selectivity, has been reported, providing a valuable tool for functional studies on TLX.
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.
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