Identification of Phelligridin-Based Compounds as Novel Human CD73 Inhibitors

Area of Science:

• Immunology
• Pharmacology
• Computational Chemistry

Background:

• CD73 is an emerging immune checkpoint that plays a role in antitumor immunity.
• Inhibiting CD73 enzymatic activity can enhance the immune response against tumors.
• Existing CD73 inhibitors are not yet suitable for clinical use, necessitating the discovery of novel candidates.

Purpose of the Study:

• To identify novel CD73 inhibitors with drug-like properties using computational and experimental approaches.
• To evaluate the potential of identified compounds as drug candidates for cancer immunotherapy.

Main Methods:

• Structure-based virtual screening of 500 molecules from the Chemdiv-Plus database.
• Analysis of drug properties to select 68 small molecules with oral, non-CNS drug profiles.
• Enzymatic assays to determine CD73 inhibition rates and IC50 values for selected compounds.

Main Results:

• Eighteen molecules exhibited significant CD73 inhibition (>20% at 100 μM).
• Eight compounds showed dose-dependent inhibition with IC50 values ranging from 6.72 to 172.1 μM.
• Phelligridin-based compounds demonstrated the most promising inhibitory activity and favorable binding modes with CD73.

Conclusions:

• Novel CD73 inhibitors with good drug properties were identified, serving as potential lead compounds for drug development.
• The identified inhibitors, particularly phelligridin derivatives, offer a promising avenue for developing CD73-targeting cancer immunotherapies.
• Understanding the binding modes provides valuable insights for the rational design of future phelligridin-based CD73 inhibitors.