| Autor: |
Dong J; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States., Jassim BA; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States., Milholland KL; Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, United States., Qu Z; Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States., Bai Y; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States., Miao Y; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States., Miao J; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States., Ma Y; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States., Lin J; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States., Hall MC; Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, United States.; Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.; Institute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.; Institute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United States., Zhang ZY; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.; Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.; Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.; Institute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.; Institute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United States. |
| Abstrakt: |
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. |
