Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer...

Area of Science:

• Immunology
• Medicinal Chemistry
• Oncology

Background:

• Retinoic acid receptor-related orphan receptor γt (RORγt) is crucial for T-helper 17 (Th17) cell differentiation and interleukin-17 (IL-17) production.
• Activation of RORγt-expressing T cells within the tumor microenvironment enhances anti-tumor immunity.
• RORγt agonists represent a potential strategy for cancer immunotherapy.

Purpose of the Study:

• To design, synthesize, and evaluate novel biaryl amide derivatives as RORγt agonists.
• To identify a potent and metabolically stable RORγt agonist for cancer treatment.

Main Methods:

• Structure-based drug design and optimization starting from RORγt inverse agonist GSK805.
• Synthesis and in vitro evaluation of biaryl amide derivatives for RORγt agonist activity.
• In vivo pharmacokinetic studies and efficacy evaluation in preclinical tumor models.

Main Results:

• Discovery of a novel RORγt agonist lead compound, designated 14.
• Compound 14 exhibited potent and selective RORγt agonist activity with improved metabolic stability.
• Excellent in vivo pharmacokinetic profiles and robust anti-tumor efficacy in B16F10 melanoma and LLC lung adenocarcinoma models.

Conclusions:

• Compound 14 is a promising RORγt agonist lead with potential for cancer immunotherapy.
• Further investigation of compound 14 is warranted for its therapeutic application.
• The developed biaryl amide scaffold represents a viable starting point for RORγt agonist discovery.