Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties.
J Med Chem
; 67(3): 2152-2164, 2024 02 08.
Article
in En
| MEDLINE
| ID: mdl-38237049
ABSTRACT
Retinoid X receptors (RXRs, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration, and metabolic diseases, but traditional RXR agonists mimicking the natural ligand 9-cis retinoic acid exhibit poor physicochemical properties, pharmacokinetics, and safety profiles. Improved RXR ligands are needed to exploit RXR modulation as a promising therapeutic concept in various indications beyond its current role in second-line cancer treatment. Here, we report the co-crystal structure of RXR in complex with a novel pyrimidine-based ligand and the structure-informed optimization of this scaffold to highly potent and highly soluble RXR agonists. Focused structure-activity relationship elucidation and rigidization resulted in a substantially optimized partial RXR agonist with low nanomolar potency, no cytotoxic activity, and very favorable physicochemical properties highlighting this promising scaffold for the development of next-generation RXR targeting drugs.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neoplasms
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
J Med Chem
/
J. med. chem
/
Journal of medicinal chemistry
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: