Abstract：
Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) control protein tyrosine phosphorylation and regulate numerous cellular functions. Dysregulated PTP activity is associated with the onset of multiple human diseases. Nevertheless, understanding of the physiological function and disease biology of most PTPs remains limited, largely due to the lack of PTP-specific chemical probes. In this study, starting from a well-known nonhydrolyzable phosphotyrosine (pTyr) mimetic, phosphonodifluoromethyl phenylalanine (F2Pmp), we synthesized 7 novel phosphonodifluoromethyl-containing bicyclic/tricyclic aryl derivatives with improved cell permeability and potency toward various PTPs. Furthermore, with fragment- and structure-based design strategies, we advanced compound 9 to compound 15, a first-in-class, potent, selective, and bioavailable inhibitor of human CDC14A and B phosphatases. This study demonstrates the applicability of the fragment-based design strategy in creating potent, selective, and bioavailable PTP inhibitors and provides a valuable probe for interrogating the biological roles of hCDC14 phosphatases and assessing their potential for therapeutic interventions.
摘要：
连同蛋白酪氨酸激酶，蛋白质酪氨酸磷酸酶（PTP）控制蛋白质酪氨酸磷酸化并调节许多细胞功能。PTP活性失调与多种人类疾病的发作有关。然而，对大多数PTP的生理功能和疾病生物学的理解仍然有限，主要是由于缺乏PTP特异性化学探针。在这项研究中,从众所周知的不可水解的磷酸酪氨酸（pTyr）模拟物开始，膦二氟甲基苯丙氨酸(F2Pmp)，我们合成了7种新型的含膦二氟甲基的双环/三环芳基衍生物，具有改善的细胞渗透性和对各种PTP的效力。此外，采用基于碎片和结构的设计策略，我们将化合物9推进到化合物15，这是一流的，强力，选择性,和人CDC14A和B磷酸酶的生物可利用性抑制剂。这项研究证明了基于片段的设计策略在创建有效的、选择性,和生物可利用的PTP抑制剂，并为询问hCDC14磷酸酶的生物学作用和评估其治疗干预潜力提供了有价值的探针。
