Protein tyrosine phosphatase inhibitors: Rational design and combinatorial synthesis

Protein tyrosine phosphatases are important biological components in signal transduction pathways. They regulate the structure and function of proteins by working as a negative regulator of protein tyrosine phosphorylation. Defective or inappropriate PTPase operation can result in diseases such as diabetes, cancers and immune dysfunctions. Therefore, PTPase inhibitors could be utilized not only as intracellular probes for PTPase functional studies, but also as the basis for the design of potential drug candidates.; alpha-Ketocarboxylic acids are inhibitors of the PTPases. To enhance their binding potency and specificity, we incorporated an aryl alpha-ketocarboxylic acid moiety into a hexapeptide template Ac-DADE-X-L-NH2. The resulting peptidic inhibitor is one of the most potent peptidic inhibitors containing a monoanionic pTyr analogue. Derivatives of squaric acids are identified as a new class of monoanionic inhibitors for PTPases. Both strong electron-withdrawing groups and larger aromatic groups in the inhibitors are beneficial to potency.; Based on the discovery that PTP1B has a secondary noncatalytic binding site, a library of 67 bidentate PTPase inhibitors that are based on the alpha-ketocarboxylic acid motif were synthesized using parallel solution-phase methods. Two aryl alpha-ketocarboxylic acids were tethered to a variety of different diamine linkers through amide bonds. Six compounds were to found to have IC50 values in the low micromolar range against the Yersinia PTPase, PTP1B, and TCPTP, and showed good selectivity for PTP1B over LAR, with modest selectivity over CD45. Aromatic groups in the linker can play an important role in determining binding affinity in this class of inhibitors.; We utilized click chemistry to generate a library of 56 PTPase inhibitors by connecting aryl alpha-ketocarboxylic acids to a variety of different alkynes. Based on the screening results, one compound was chosen as the lead for the second round of library generation. The best inhibitor gave nanomolar IC50 values against the Yersinia PTPase, and single-digit micromolar IC50 values against PTP1B and TCPTP, representing approximately 400-fold increase in potency over the simple alpha-ketoacid. It showed good selectivity for PTP1B over LAR and modest selectivity over CD45.