Potent Competitive Inhibitors of Ecto-5'-nucleotidase (CD73) based on 6‑(Het)aryl-7-deazapurine Ribonucleoside...

Area of Science:

• Medicinal Chemistry
• Cancer Immunotherapy
• Enzyme Inhibition

Background:

• CD73 is a key enzyme in the tumor microenvironment, generating immunosuppressive adenosine.
• Targeting CD73 offers a promising strategy for enhancing cancer immunotherapy.
• Adenosine produced by CD73 promotes tumor immune evasion.

Purpose of the Study:

• To design and synthesize novel 2-substituted 7-deazapurine ribonucleoside 5'-O-bisphosphonates.
• To evaluate the CD73 inhibition activity and selectivity of these compounds.
• To optimize compounds for favorable pharmacokinetic properties and in vitro efficacy.

Main Methods:

• Systematic design and synthesis of diverse 7-deazapurine derivatives.
• Biochemical assays to determine CD73 inhibition potency (K_i) and selectivity (vs. CD39, NTPDase3).
• Cell-based assays to assess adenosine suppression, T cell activation, and cytotoxicity.

Main Results:

• Discovered highly potent and selective CD73 inhibitors with single-digit picomolar K_i values.
• Identified optimal structures featuring bicyclic (het)-aryl groups at position 6 and chlorine at position 2.
• Optimized compounds demonstrated low clearance, long half-life, high solubility, and effective adenosine suppression in cells.
• Compounds rescued CD8+ T cell activation and were non-toxic to human fibroblasts.

Conclusions:

• Novel 7-deazapurine bisphosphonates are potent and selective CD73 inhibitors.
• These inhibitors exhibit promising pharmacokinetic profiles and in vitro anti-tumor immune activity.
• The developed compounds represent potential next-generation therapeutics for cancer immunotherapy, comparable to AB680.