Synthesis and biological evaluation of a targeted library of protein phosphatase inhibitors

Phosphorylation of serine, threonine, and tyrosine controls fundamental mam malian cell events and is achieved by kinases which, in turn, are in dynami c relationship with phosphatases. Few selective inhibitors of protein tyros ine and dual specificity phosphatases are readily available. Based on SAR s tudies of naturally occurring phosphatase inhibitors and following up on pr eviously published research, we have designed a new pharmacophore model V a nd synthesized a new library of functional analogues of V. All synthetic st eps were carried out and optimized employing combinatorial chemistry method s on Wang resin. All compounds were tested in vitro for their ability to in hibit recombinant human protein tyrosine (PTP1B) and dual-specificity (Cdc2 5B(2) and VHR) phosphatases. Th ree of the approximately 70 compounds in ou r library inhibited Cdc25B(2) by 50% at 375-490 mu M. No compounds inhibite d PTP1B, and only one blocked VHR. Cell-culture studies revealed no toxicit y to human breast cancer cells with two of the phosphatase inhibitors. (C) 2000 John Wiley & Sons, Inc.