Discovery of\n(2<i>R</i>,4<i>R</i>)‑4-((<i>S</i>)‑2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic\nAcid (AZD0011), an Actively Transported Prodrug of a Potent Arginase\nInhibitor to Treat Canc

Arginase is a promising immuno-oncology target that can\nrestore\nthe innate immune response. However, it’s highly polar active\nsite often requires potent inhibitors to mimic amino acids, leading\nto poor passive permeability and low oral exposure. Using structure-based\ndrug design, we discovered a novel proline-based arginase inhibitor\n(<b>10</b>) that was potent but had low oral bioavailability\nin rat. This issue was addressed by incorporating amino acids to target\nPepT1/2 active transport, followed by in vivo hydrolysis post absorption.\nThe hydrolysis rate was highly tunable, and the valine prodrug (<b>19</b>) showed the best balance of stability and exposure of the\npotent payload. Dosing of <b>19</b> in mouse xenograft models\nsignificantly increased arginine in the tumor microenvironment, resulting\nin tumor growth inhibition as a monotherapy and in combination with\nan anti-PD-L1 antibody. Compound <b>19</b> (AZD0011) displays\ngood pharmacokinetics and was selected as a clinical drug candidate\nfor cancer.