Aryl alkyl ether CD73 inhibitor LB10 is orally active in a lung cancer model
- CD73 is the rate-limiting enzyme of the adenosine pathway and a tumor-immunosuppression target.
- An aryl alkyl ether series was designed; LB10 emerged as the most promising, potent in both biochemical and cell assays.
- Enzyme kinetics and co-crystallography confirmed competitive inhibition.
- LB10 had low cytotoxicity and good pharmacokinetics, and oral dosing curbed tumor growth in a syngeneic Lewis lung carcinoma model, alone or in combination.
💡 Points
Non-nucleotide CD73 inhibitors that stay orally bioavailable are the part I care about: most potent early chemotypes were AMP-like and carried the usual permeability and clearance baggage. A co-crystal confirming a competitive mode gives a clean starting point for SAR around the ether linker. I would want to see how it behaves against the soluble versus membrane-bound enzyme and in human-relevant adenosine readouts before getting excited.