Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers

Area of Science:

• Medicinal Chemistry
• Oncology
• Dermatology

Background:

• Rexinoid 1 shows promise in cancer chemoprevention but causes hypertriglyceridemia.
• Developing analogs to dissociate anti-cancer activity from lipid toxicity is crucial.

Purpose of the Study:

• To synthesize and evaluate novel rexinoid analogs of compound 1.
• To identify rexinoids with potent anticancer activity and reduced lipid toxicity.

Main Methods:

• Synthesis of four new rexinoid analogs.
• Assessment of triglyceride levels.
• Retinoid X receptor (RXR) binding affinity studies.
• Evaluation of anti-inflammatory and anti-cancer effects in vitro and in vivo.
• Biophysical studies (hRXRα-LBD complex).

Main Results:

• Three analogs demonstrated no elevation in serum triglycerides.
• Rexinoids 3 and 4 exhibited twice the binding potency to RXR compared to compound 1.
• Rexinoids 3-6 effectively upregulated genes for all-trans retinoic acid (ATRA) biosynthesis.
• Rexinoids 3 and 4 significantly reduced LPS-induced inflammation and prevented UVB-induced nonmelanoma skin cancer (NMSC).
• Biophysical studies revealed distinct conformational and dynamic differences in the ligand-binding domain.

Conclusions:

• Novel rexinoids (3 and 4) effectively prevent skin cancer with reduced toxicity.
• These analogs offer a promising therapeutic strategy for cancer chemoprevention.
• Understanding ligand-RXR interactions is key for developing safer and more effective rexinoids.