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

Abstract

Phosphorylation of serine, threonine, and tyrosine controls fundamental mammalian cell events and is achieved by kinases which, in turn, are in dynamic relationship with phosphatases. Few selective inhibitors of protein tyrosine and dual specificity phosphatases are readily available. Based on SAR studies of naturally occurring phosphatase inhibitors and following up on previously published research, we have designed a new pharmacophore model V and synthesized a new library of functional analogues of V. All synthetic steps were carried out and optimized employing combinatorial chemistry methods on Wang resin. All compounds were tested in vitro for their ability to inhibit recombinant human protein tyrosine (PTP1B) and dual‐specificity (Cdc25B2 and VHR) phosphatases. Three of the approximately 70 compounds in our library inhibited Cdc25B2 by 50% at 375–490 μM. No compounds inhibited PTP1B, and only one blocked VHR. Cell‐culture studies revealed no toxicity to human breast cancer cells with two of the phosphatase inhibitors. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 71:58–70, 2000.

Synthesis of a Tetronic Acid Library Focused on Inhibitors of Tyrosine and Dual-Specificity Protein Phosphatases and Its Evaluation Regarding VHR and Cdc25B Inhibition

“…As a result, compound 30 exhibited a strong inhibition of cdc25B (IC 50 = 0.4 μM) and a 30-fold preference for cdc25B compared to VHR. To our knowledge, 27 − 30 are the most potent class of inhibitors among the reported cdc25 inhibitors 2 Inhibition of Cdc25B compoundIC 50 (μM)compoundIC 50 (μM) 1 2.2 ± 0.0 21 1.6 ± 0.3 ent- 1 5.1 ± 0.3 22 >125 2 0.90 ± 0.03 23 2.2 ± 0.1 3 32.1 ± 3.8 24 6.2 ± 0.2 4 7.9 ± 0.8 25 1.2 ± 0.2 7 3.6 ± 0.2 26 3.0 ± 0.2 11 18.0 ± 0.9 27 0.38 ± 0.02 12 11.5 ± 0.9 28 0.52 ± 0.03 13 35.0 ± 0.4 29 0.6 ± 0.0 14 100.8 ± 8.0 30 0.40 ± 0.0 15 26.2 ± 0.1 31 >125 16 >125 32 >125 17 >125 33 1.4 ± 0.1 18 22.9 ± 0.3 34 1.1 ± 0.0 19 2.0 ± 0.0 35 3.7 ± 0.3 20 3.3 ± 0.2 36 3.0 ± 0.1 …”

“…The first natural products reported to inhibit cdc25B were dnacin A1 and B1 (IC 50 = 141 and 64.4 μM), but these compounds are also known to cause DNA damage and other synthetic carboxylic acid derivatives were reported to inhibit cdc25s with IC 50 of micromolar orders . The development of more potent inhibitors of cdc25 is still in great demand.…”

Inhibitors for Proteins Endowed with Catalytic and Non-Catalytic Activity which Recognize pTyr

“…11)] designed with the aid of SAR available for the natural products Microcystin LR and Calyculin A [100]. Several compounds showed interesting activities: among these, SCααδ9 [31a, (Fig.…”