Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy.

Szczepankiewicz BG, Liu G, Hajduk PJ, Abad-Zapatero C, Pei Z, Xin Z, Lubben TH, Trevillyan JM, Stashko MA, Ballaron SJ, Liang H, Huang F, Hutchins CW, Fesik SW, Jirousek MR
J Am Chem Soc. 2003 125 (14): 4087-96

PMID: 12670229 · DOI:10.1021/ja0296733

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.

MeSH Terms (16)

Amino Acid Sequence Binding, Competitive Binding Sites Catalysis Drug Design Enzyme Inhibitors Kinetics Ligands Models, Molecular Molecular Sequence Data Nuclear Magnetic Resonance, Biomolecular Oxamic Acid Protein Conformation Protein Tyrosine Phosphatase, Non-Receptor Type 1 Protein Tyrosine Phosphatases Structure-Activity Relationship

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