The phosphatase of regenerating liver (PRL) family, also known as protein tyrosine phosphatase 4A (PTP4A), are dual-specificity phosphatases with largely unknown cellular functions. However, accumulating evidence indicates that PRLs are oncogenic across a broad variety of human cancers. PRLs are highly expressed in advanced tumors and metastases compared to early stage cancers or matched healthy tissue, and high expression of PRLs often correlates with poor patient prognosis. Consequentially, PRLs have been considered potential therapeutic targets in cancer. Persistent efforts have been made to define their role and mechanism in cancer progression and to create specific PRL inhibitors for basic research and drug development. However, targeting PRLs with small molecules remains challenging due to the highly conserved active site of protein tyrosine phosphatases and a high degree of sequence similarity between the PRL protein families. Here, we review the current PRL inhibitors, including the strategies used for their identification, their biological efficacy, potency, and selectivity, with a special focus on how PRL structure can inform future efforts to develop specific PRL inhibitors.

再生肝（PRL）家族的磷酸酶，也称为蛋白质酪氨酸磷酸酶4A（PTP4A），是具有特异性未知的细胞功能的双重特异性磷酸酶。但是，越来越多的证据表明PRL在多种人类癌症中都是致癌的。与早期癌症或匹配的健康组织相比，PRL在晚期肿瘤和转移灶中高表达，而PRLs的高表达通常与患者预后不良相关。因此，PRL被认为是癌症的潜在治疗靶标。为了确定其在癌症进展中的作用和机制，并为基础研究和药物开发创建特定的PRL抑制剂，已经做出了持续的努力。然而，由于蛋白质酪氨酸磷酸酶的高度保守的活性位点和PRL蛋白质家族之间的高度序列相似性，用小分子靶向PRL仍然具有挑战性。在这里，我们回顾了当前的PRL抑制剂，包括用于鉴定它们的策略，其生物学功效，效力和选择性，并特别关注PRL的结构如何为将来开发特定PRL抑制剂的努力提供信息。