Development of Novel Phosphonodifluoromethyl-Containing Phosphotyrosine Mimetics and a First-In-Class, Potent, Selective, and Bioavailable Inhibitor of Human CDC14 PhosphatasesClick to copy article linkArticle link copied!
- Jiajun DongJiajun DongBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Jiajun Dong
- Brenson A. JassimBrenson A. JassimBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Brenson A. Jassim
- Kedric L. MilhollandKedric L. MilhollandDepartment of Biochemistry, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Kedric L. Milholland
- Zihan QuZihan QuDepartment of Chemistry, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Zihan Qu
- Yunpeng BaiYunpeng BaiBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Yunpeng Bai
- Yiming MiaoYiming MiaoBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Yiming Miao
- Jinmin MiaoJinmin MiaoBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Jinmin Miao
- Yuan MaYuan MaBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Yuan Ma
- Jianping LinJianping LinBorch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Jianping Lin
- Mark C. HallMark C. HallDepartment of Biochemistry, Purdue University, West Lafayette, Indiana 47907, United StatesInstitute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United StatesInstitute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United StatesInstitute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Mark C. Hall
- Zhong-Yin Zhang*Zhong-Yin Zhang*Email: [email protected]Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United StatesDepartment of Chemistry, Purdue University, West Lafayette, Indiana 47907, United StatesInstitute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United StatesInstitute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United StatesInstitute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, Indiana 47907, United StatesMore by Zhong-Yin Zhang
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.
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