Potent Competitive Inhibitors of Ecto-5′-nucleotidase (CD73) based on 6-(Het)aryl-7-deazapurine Ribonucleoside 5′- O -Bisphosphonates

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Abstract
CD73 generates immunosuppressive adenosine in the tumor microenvironment and is a promising target for cancer immunotherapy. We have designed and systematically studied diverse 2-substituted 7-deazapurine ribonucleoside 5'-O-bisphosphonates bearing a variety of (het)-aryl groups at position 6 and discovered their highly potent and selective CD73 inhibition activity. The most active compounds (with single-digit picomolar K i) contained bicyclic (het)-aryl groups at position 6 in combination with chlorine at position 2. Further optimization of pharmacokinetic properties identified inhibitors with low clearance, long half-life, high solubility, and excellent selectivity over CD39 and NTPDase3. They effectively suppressed adenosine formation in MDA-MB-231 cells, rescued CD8+ T cell activation, and were nontoxic to human fibroblasts. Overall, their profile compares favorably with AB680, a CD73 inhibitor currently in phase I/II clinical trials.
Funding Information
  • Agentura Pro Zdravotnický Výzkum České Republiky (NU22-03-00318)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (LX22NPO5102)
  • Grantová Agentura České Republiky (24-10814S)

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