Law Mary E, Dulloo Zaafir M, Hardy Brian, Kelegama Ania, Clark Reagan, Rivas Montbrun Mariana, Antmann Gabriella, Nooka Srihith, Castellano Ronald K, Law Brian K
Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL 32610, USA.
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
Biomolecules. 2025 Aug 8;15(8):1146. doi: 10.3390/biom15081146.
Protein Disulfide Isomerases (PDIs) are emerging targets in anticancer therapy, with several PDI inhibitors demonstrating anticancer efficacy in preclinical models. Research has largely focused on "canonical" PDIs, such as PDIA1, which contain CXXC active site motifs where C represents Cysteine. Canonical PDIs have well-studied, critical roles in forming, breaking, and exchanging/scrambling disulfide bonds during protein folding. In contrast, non-canonical PDIs, which harbor CXXS active site motifs, remain less well-studied despite their role as sensors or effectors of protein folding quality control during protein trafficking in the secretory pathway. Here, we provide a review of the literature relating to the non-canonical PDIs ERp44, AGR2, and AGR3, which have been identified as strong dependencies in specific cancer subtypes according to the DepMap database. The biological and biochemical functions of ERp44, AGR2, and AGR3 are discussed, highlighting the role of ERp44 in two mechanisms of protein folding quality control, AGR2 as a selective sensor of mucin protein misfolding, and a unique role for AGR3 in cilia. Finally, we discuss recent efforts to develop small molecule inhibitors of ERp44, AGR2, and AGR3 as tool compounds and experimental therapeutics.
蛋白质二硫键异构酶（PDIs）正成为抗癌治疗中的新兴靶点，几种PDI抑制剂已在临床前模型中显示出抗癌疗效。研究主要集中在“经典”PDIs上，如PDIA1，其含有CXXC活性位点基序，其中C代表半胱氨酸。经典PDIs在蛋白质折叠过程中形成、断裂和交换/重排二硫键方面发挥着经过充分研究的关键作用。相比之下，具有CXXS活性位点基序的非经典PDIs尽管在分泌途径中蛋白质运输过程中作为蛋白质折叠质量控制的传感器或效应器发挥作用，但研究较少。在这里，我们综述了与非经典PDIs ERp44、AGR2和AGR3相关的文献，根据DepMap数据库，它们已被确定为特定癌症亚型中的强依赖性靶点。我们讨论了ERp44、AGR2和AGR3的生物学和生化功能，强调了ERp44在两种蛋白质折叠质量控制机制中的作用，AGR2作为粘蛋白错误折叠的选择性传感器，以及AGR3在纤毛中的独特作用。最后，我们讨论了最近开发ERp44、AGR2和AGR3小分子抑制剂作为工具化合物和实验性治疗药物的努力。
