Second-Generation CD73 Inhibitors Based on a 4,6-Biaryl-2-thiopyridine Scaffold

Area of Science:

• Medicinal Chemistry
• Immunology
• Biochemistry

Background:

• Ecto-5 -nucleotidase (CD73) plays a crucial role in adenosine production, which mediates immune suppression.
• Targeting CD73 is a promising strategy for cancer immunotherapy by reversing immunosuppression.
• Developing novel CD73 inhibitors requires exploring new chemical scaffolds and understanding assay discrepancies.

Purpose of the Study:

• To synthesize and evaluate novel 4,6-biaryl-2-thiopyridine derivatives as potential CD73 inhibitors.
• To investigate the structure-activity relationships of these derivatives in inhibiting CD73.
• To assess the ability of these compounds to reverse adenosine-mediated immune suppression in human T cells.

Main Methods:

• Synthesis of 4,6-biaryl-2-thiopyridine derivatives via coupling reactions.
• Evaluation of CD73 inhibition using purified recombinant protein and cell-based assays.
• Assessment of immune suppression reversal in human T cells.

Main Results:

• Eighteen new 4,6-biaryl-2-thiopyridine derivatives were synthesized.
• Divergent results were observed between purified protein and cell-based CD73 inhibition assays.
• Three derivatives with morpholino substituents demonstrated the ability to reverse adenosine-mediated immune suppression.
• The most potent compounds achieved total or partial reversion of immune suppression at specific concentrations.

Conclusions:

• The synthesized 4,6-biaryl-2-thiopyridine derivatives represent a novel chemotype of CD73 allosteric inhibitors.
• The study highlights challenges in targeting CD73 due to its soluble and membrane-bound forms.
• These compounds show potential for modulating immune responses in therapeutic applications.