Development of Novel Phosphonodifluoromethyl-Containing Phosphotyrosine Mimetics and a First-In-Class, Potent, Selective, and Bioavailable Inhibitor of Human CDC14 Phosphatases

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.