Development of Protein Phosphatases Inhibitors: A Focused Library Approach.

Abstract

Selective inhibitors of protein phosphatases are expected to be useful tools for clarifying the biological functions of the phosphatases themselves, and also candidates for novel therapeutics. In terms of the catalytic site structure, protein phosphatases can be divided into two large groups: one is the protein serine/threonine phosphatases (PPs) group, and the other is the protein phosphatases (PTPs)/dual-specificity phosphatases (DSPs) group. We planned a library approach to the identification of PP- or PTP/DSP-selective inhibitors, in which unique structures derived from natural products are used as “core” phosphate mimics. In this paper we describe a synthesis and evaluation of a PTP/DSP inhibitor-oriented library. A series of novel tetronic acid derivatives were synthesized and evaluated as inhibitors of the dual-specificity protein phosphatases VHR and cdc25B, and tyrosine phosphatase PTP-S2. Several compounds were found to be potent inhibitors of cdc25B which is a key enzyme for cell-cycle progression.