Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.
Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.
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靶向蛋白磷酸酶用于癌症免疫治疗和自身免疫性疾病。
DOI：
10.1038/s41573-022-00618-w
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发表时间：
2023-04
影响因子：
120.1
通讯作者：
Bottini, Nunzio
中科院分区：
文献类型：
--
作者：
Stanford, Stephanie M. M.;Bottini, Nunzio
蛋白磷酸酶是多种重要细胞过程的关键调节因子，是多种疾病有吸引力的治疗靶点。尽管人们在磷酸酶靶向药物的发现方面付出了巨大的努力，但竞争性磷酸酶抑制剂的早期探索却受到成药性问题的困扰，导致磷酸酶被视为困难靶点。尽管面临挑战，但经过不懈的努力，我们已经鉴定出了其中一些酶的几种药物样、非竞争性调节剂——包括含有 SH2 结构域的蛋白酪氨酸磷酸酶 2、蛋白酪氨酸磷酸酶 1B、血管内皮蛋白酪氨酸磷酸酶和蛋白磷酸酶 1——重新激发了人们对磷酸酶治疗靶向的兴趣。在这里，我们讨论磷酸酶药物发现的最新进展，重点是具有生物活性的选择性调节剂的开发。评估了蛋白磷酸酶在免疫细胞中的作用和调节及其作为免疫肿瘤学和自身免疫适应症的强大靶标的潜力。蛋白质磷酸化失调与许多人类疾病有关，但传统上证明靶向蛋白质磷酸盐具有挑战性。在这里，斯坦福和博蒂尼概述了蛋白磷酸酶家族，重点关注它们在自身免疫和肿瘤免疫中的作用。对解决这些目标的新兴战略和正在开发的药物进行了评估。
Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes — including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 — reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed. Dysregulated protein phosphorylation is implicated in numerous human diseases, but targeting protein phosphates has traditionally proved challenging. Here, Stanford and Bottini provide an overview of protein phosphatase families, focusing on their roles in autoimmunity and tumour immunity. Emerging strategies to tackle these targets and agents in development are assessed.
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