Structure-Based Discovery of Proline-Derived Arginase Inhibitors

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology, by Min Lu*, Hongjun Zhang, Derun Li, Matthew Childers, Qinglin Pu, Rachel L. Palte, Symon Gathiaka, Thomas W. Lyons, Anandan Palani, Peter W. Fan, Peter Spacciapoli, J. Richard Miller, Hyelim Cho, Mangeng Cheng, Kalyan Chakravarthy, Jennifer O’Neil, Padmanabhan Eangoor, Adam Beard, Hai-Young Kim, Josep Saurí, Hakan Gunaydin, David L. Sloman, Phieng Siliphaivanh, Jared Cumming, and Christian Fischer. ACS Med. Chem. Lett. 2021, 12, 9, 1380–1388. https://doi.org/10.1021/acsmedchemlett.1c00195

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.