Discovery of (2R,4R)‑4-((S)‑2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic Acid (AZD0011), an Actively Transported Prodrug of a Potent Arginase Inhibitor to Treat Cancer

Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it’s highly polar active site often requires potent inhibitors to mimic amino acids, leading to poor passive permeability and low oral exposure. Using structure-based drug design, we discovered a novel proline-based arginase inhibitor (10) that was potent but had low oral bioavailability in rat. This issue was addressed by incorporating amino acids to target PepT1/2 active transport, followed by in vivo hydrolysis post absorption. The hydrolysis rate was highly tunable, and the valine prodrug (19) showed the best balance of stability and exposure of the potent payload. Dosing of 19 in mouse xenograft models significantly increased arginine in the tumor microenvironment, resulting in tumor growth inhibition as a monotherapy and in combination with an anti-PD-L1 antibody. Compound 19 (AZD0011) displays good pharmacokinetics and was selected as a clinical drug candidate for cancer.