A combinatorial strategy for the acquisition of potent and specific protein tyrosine phosphatase inhibitors.

Protein tyrosine phosphatases (PTPs), a large family of signaling enzymes, regulate many cellular processes, such as proliferation, differentiation, migration, apoptosis, and immune responses. Small molecule inhibitors against PTPs are valuable both as powerful tools to study the functions of target PTPs and as lead compounds for pharmacological development. Here, we describe a novel combinatorial library approach to target simultaneously both the active site pocket and a peripheral secondary binding site for the acquisition of potent and specific PTP inhibitors. Fluorescence tagging during combinatorial library synthesis enables fluorescence polarization-based high-throughput screening of the resulting library, leading to identification of a TC-PTP inhibitor.