Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy.
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
J Med Chem. 2024 Nov 28;67(22):19988-20021. doi: 10.1021/acs.jmedchem.4c01429. Epub 2024 Nov 18.
The overexpression of two arginase (ARG) isoforms, ARG1 and ARG2, contributes to the onset of numerous disorders, including cardiovascular and immune-mediated diseases, as well as tumors. To elucidate the specific roles of ARG1 and ARG2 without interfering with their physiological functions, it is crucial to develop effective ARG inhibitors that target only one isoform, while maintaining low toxicity and an adequate pharmacokinetic profile. In this context, we present a comprehensive overview of the different generations of ARG inhibitors. Given the general lack of selectivity in most existing inhibitors, we analyzed the structural features and plasticity of the ARG1 and ARG2 binding sites to explore the potential for designing inhibitors with novel binding patterns. We also review ongoing preclinical and clinical studies on selected inhibitors, highlighting both progress and challenges in developing potent, selective ARG inhibitors. Furthermore, we discuss medicinal chemistry strategies that may accelerate the discovery of selective ARG inhibitors.
两种精氨酸酶 (ARG) 同工型，ARG1 和 ARG2 的过度表达导致了许多疾病的发生，包括心血管和免疫介导的疾病以及肿瘤。为了阐明 ARG1 和 ARG2 的特定作用而不干扰其生理功能，开发仅针对一种同工型的有效 ARG 抑制剂至关重要，同时保持低毒性和适当的药代动力学特征。在这方面，我们全面概述了不同代的 ARG 抑制剂。鉴于大多数现有抑制剂普遍缺乏选择性，我们分析了 ARG1 和 ARG2 结合位点的结构特征和可塑性，以探索设计具有新型结合模式抑制剂的潜力。我们还回顾了选定抑制剂的正在进行的临床前和临床研究，强调了开发有效、选择性 ARG 抑制剂的进展和挑战。此外，我们还讨论了可能加速发现选择性 ARG 抑制剂的药物化学策略。
