Design, Synthesis, and Characterization of Globular Orphan Nuclear Receptor Regulator with Biological Activity in...

Area of Science:

• Oncology
• Pharmacology
• Nanotechnology

Background:

• Sarcomas are rare, heterogeneous cancers with poor prognosis due to genetic complexity and uncertain origins.
• Existing treatments for sarcomas face challenges owing to their inherent heterogeneity and resistance mechanisms.

Purpose of the Study:

• To identify a novel retinoid X receptor (RXR) agonist for sarcoma treatment using structure-based drug discovery.
• To develop and evaluate the efficacy and safety of self-assembling nanoparticles (Nano-RXR) encapsulating the identified RXR agonist.

Main Methods:

• Structure-based drug discovery and computational modeling were employed to identify a bis(indolyl)methane scaffold as an RXR agonist.
• The identified agent was co-self-assembled with an amphiphilic diblock copolymer into stable nanoparticles (Nano-RXR).
• Efficacy and safety were assessed in transformed pig sarcoma cells (63-3 Cre and 141-10 Cre) and rodent xenograft models, including "Oncopig" models.

Main Results:

• The developed Nano-RXR demonstrated potent RXR agonistic activity, confirmed by gene and protein expression analysis.
• Nano-RXR effectively modulated metabolic and transporter genes associated with orphan nuclear receptors in sarcoma models.
• Significant modulation of programmed cell death pathways was observed in Oncopig sarcoma models treated with Nano-RXR.

Conclusions:

• Structure-based drug discovery successfully identified a novel RXR agonist for sarcoma therapy.
• Nano-RXR nanoparticles represent a stable and effective drug delivery system for sarcoma treatment.
• This approach shows promise in targeting key pathways, including programmed cell death, for improved sarcoma outcomes.