Methods toward the development of protein tyrosine phosphatase inhibitors.

摘要

Post-translational phosphorylation of proteins is a common modification employed by cells to regulate enzyme activity and signal transduction. Protein tyrosine phosphatases (PTPases) encompass a large family of enzymes that catalyze the dephosphorylation of phosphotyrosine residues on intracellular proteins. Recent studies have shown that several PTPases are potential therapeutic targets for the treatment of diseases including type II diabetes and the bubonic plague. Hence, there is considerable interest in the development of potent, specific PTPase inhibitors.; We identified aryl alpha-ketocarboxylic acids and sulfonamides as novel inhibitors of the Yersinia PTPase and different approaches were taken to enhance the specificity and potency of these classes of compounds. In the first method, the phosphotyrosine residue of a peptidic high-affinity PTPase substrate was replaced by a phenylalanine derivative containing a sulfonamide group. In the second approach, multivalent compounds containing two or three aryl alpha-ketoacids tethered to an aromatic linker were designed to simultaneously interact with the active site and a secondary binding site that is present in certain PTPases including PTP1B and the Yersinia PTPase.; The multivalency approach led to the discovery of potent inhibitors of the Yersinia PTPase and PTP1B with good selectivity for these two phosphatases over LAR. Using the bidentate alpha-ketoacid motif as a core structure, a library of 104 compounds was synthesized by parallel solution-phase methods and screened against the Yersinia PTPase and PTP1B. Four members of the library were selected for further investigation and a nanomolar-level PTP1B inhibitor was identified. This compound represents a greater than 120-fold increase in potency over the parent structure upon which the library was based. In general, these compounds show the greatest potency against the Yersinia PTPase, high selectivity over LAR, but modest selectivity over TCPTP and CD45. In addition, one of these compounds was found to inhibit PTP1B-catalyzed dephosphorylation of autophosphorylated insulin receptor kinase. Taken together, aryl alpha-ketoacids represent a class of small molecules that could be developed into potent, selective PTPase inhibitors and could serve as a foundation for therapeutic agents or mechanistic tools to define PTPase functions.