436864-52-7Relevant articles and documents
Convergent Protein Phosphatase Inhibitor Design for PTP1B and TCPTP: Exchangeable Vanadium Coordination Complexes on Graphene Quantum Dots
Feng, Bo,Dong, Yaqiong,Shang, Bing,Zhang, Bowen,Crans, Debbie C.,Yang, Xiaoda
, (2021/11/03)
Development of potent and specific inhibitors of protein tyrosine phosphatase 1B (PTP1B) with desired drug-like properties is still a challenge. Based on the crystal structures of PTP1B transition state analog consisting of a vanadate peptide, a novel approach is proposed to design PTP1B inhibitors, in which the tyrosyl vanadate ester of a PTP1B peptide mimic (PL1) is stably integrated on the membrane permeable graphene quantum dots (GQDs). The vanadate complexes (GQD-PL1-VV) prepared exhibit high potency (Ki?= 6?± 1?× 10?9 m) and selectivity (selectivity index SI >200?for PTP1B versus the T-cell protein tyrosine phosphatase, TCPTP) in solution and in HepG2 cells. Oral administration of GQD-PL1-VV in db/db model mice shows selective PTP1B inhibition in liver and fat tissues and exhibits improved anti-diabetic activity compared to bis(maltolato)oxovanadium(IV). Moreover, exchange of PL1 to a TCPTP-specific ligand (PL2) results in potent TCPTP inhibition (Ki?= 59?± 12?× 10?9 m) as expected with SI ≈23 versus PTP1B. Overall, the present results provide a paradigm shift and a general design of phosphatase inhibitors consisting of GQDs, a complexing targeting ligand and vanadium (V) for selective regulation of PTP1B both in vitro and vivo.
PROTEIN TYROSINE PHOSPHATASE INHIBITORS AND METHODS OF USE THEREOF
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Page/Page column 36, (2008/06/13)
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Selective protein tyrosine phosphatase 1B inhibitors: Targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands
Liu, Gang,Xin, Zhili,Liang, Heng,Abad-Zapatero, Cele,Hajduk, Philip J.,Janowick, David A.,Szczepankiewicz, Bruce G.,Pei, Zhonghua,Hutchins, Charles W.,Ballaron, Stephen J.,Stashko, Michael A.,Lubben, Thomas H.,Berg, Cathy E.,Rondinone, Cristina M.,Trevillyan, James M.,Jirousek, Michael R.
, p. 3437 - 3440 (2007/10/03)
Protein tyrosine phosphatase (PTPase) 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling cascades. We identified several salicylic acid-based ligands for the second phosphotyrosine binding site of PTP1B using a NMR-based screening. Structure-based linking with a catalytic site-directed oxalylarylaminobenzoic acid-based pharmacophore led to the identification of a novel series of potent PTP1B inhibitors exhibiting 6-fold selectivity over the highly homologous T-cell PTPase (TCPTP) and high selectivity over other phosphatases.
