Opportunities\nand\nChallenges of Arginase Inhibitors\nin Cancer: A Medicinal Chemistry Perspective

The overexpression of two arginase\n(ARG) isoforms, ARG1 and ARG2,\ncontributes to the onset of numerous disorders, including cardiovascular\nand immune-mediated diseases, as well as tumors. To elucidate the\nspecific roles of ARG1 and ARG2 without interfering with their physiological\nfunctions, it is crucial to develop effective ARG inhibitors that\ntarget only one isoform, while maintaining low toxicity and an adequate\npharmacokinetic profile. In this context, we present a comprehensive\noverview of the different generations of ARG inhibitors. Given the\ngeneral lack of selectivity in most existing inhibitors, we analyzed\nthe structural features and plasticity of the ARG1 and ARG2 binding\nsites to explore the potential for designing inhibitors with novel\nbinding patterns. We also review ongoing preclinical and clinical\nstudies on selected inhibitors, highlighting both progress and challenges\nin developing potent, selective ARG inhibitors. Furthermore, we discuss\nmedicinal chemistry strategies that may accelerate the discovery of\nselective ARG inhibitors.