PTP1B Inhibition and Antihyperglycemic Activity in the ob/ob Mouse Model of Novel 11-Arylbenzo[b]naphtho[2,3-d]furans and 11-Arylbenzo[b]naphtho[2,3-d]thiophenes

Wrobel, Jay; Sredy, Janet; Moxham, Christopher M.; Dietrich, Arlene; Li, Zenan; Sawicki, Diane R.; Seestaller, Laura; Li, Wu; Katz, Alfred; Sullivan, Donald; Tio, C O; Zhang, Zhong Yin

doi:10.1021/jm990260v

Cited by 121 publications

(61 citation statements)

References 21 publications

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“…Our HTS assays preceded the assays on the docking compounds. Between running the HTS assays and testing the docking-derived compounds, we found that we were unable to reproduce literature values for the binding of several known ligands 27 with albumin present. Removing the albumin allowed us to reproduce the literature values, significantly increasing the apparent affinity of the reported inhibitors.…”

Section: Htsmentioning

confidence: 88%

Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B

et al. 2002

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High-throughput screening (HTS) of compound libraries is used to discover novel leads for drug development. When a structure is available for the target, computer-based screening using molecular docking may also be considered. The two techniques have rarely been used together on the same target. The opportunity to do so presented itself in a project to discover novel inhibitors for the enzyme protein tyrosine phosphatase-1B (PTP1B), a tyrosine phosphatase that has been implicated as a key target for type II diabetes. A corporate library of approximately 400 000 compounds was screened using high-throughput experimental techniques for compounds that inhibited PTP1B. Concurrently, molecular docking was used to screen approximately 235 000 commercially available compounds against the X-ray crystallographic structure of PTP1B, and 365 high-scoring molecules were tested as inhibitors of the enzyme.Of approximately 400 000 molecules tested in the high-throughput experimental assay, 85 (0.021%) inhibited the enzyme with IC 50 values less than 100 µM; the most active had an IC 50 value of 4.2 µM. Of the 365 molecules suggested by molecular docking, 127 (34.8%) inhibited PTP1B with IC 50 values less than 100 µM; the most active of these had an IC 50 of 1.7 µM. Structure-based docking therefore enriched the hit rate by 1700-fold over random screening. The hits from both the high-throughput and docking screens were dissimilar from phosphotyrosine, the canonical substrate group for PTP1B; the two hit lists were also very different from each other. Surprisingly, the docking hits were judged to be more druglike than the HTS hits. The diversity of both hit lists and their dissimilarity from each other suggest that docking and HTS may be complementary techniques for lead discovery.

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Section: Htsmentioning

confidence: 88%

Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B

et al. 2002

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“…The K d for compound 21B was obtained via competitive displacement of the coumarin derivative using Equation 2 (25). 50 Values-The PTPase activity was assayed using p-nitrophenyl phosphate (pNPP) as a substrate at 25°C in 50 mM 3,3-dimethylglutarate buffer, pH 7.0, containing 1 mM EDTA with an ionic strength of 0.15 M adjusted by addition of NaCl. The reaction was initiated by the addition of the enzyme to a reaction mixture (0.2 ml) containing various concentrations of pNPP and quenched after 2-3 min by addition of 0.05 ml of 5 N NaOH.…”

Section: Determination Of K D Values-mentioning

confidence: 99%

Acquisition of a Specific and Potent PTP1B Inhibitor from a Novel Combinatorial Library and Screening Procedure

Shen¹,

Keng²,

Li³

et al. 2001

Journal of Biological Chemistry

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194

156

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Protein-tyrosine phosphatases (PTPases) form a large family of enzymes that serve as key regulatory components in signal transduction pathways. Defective or inappropriate regulation of PTPase activity leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases including cancers and diabetes. For example, recent gene knockout studies in mice identify PTP1B as a promising target for anti-diabetes/obesity drug discovery. Thus, there is intense interest in obtaining specific and potent PTPase inhibitors for biological studies and pharmacological development. However, given the highly conserved nature of the PTPase active site, it is unclear whether selectivity in PTPase inhibition can be achieved. We describe a combinatorial approach that is designed to target both the active site and a unique peripheral site in PTP1B. Compounds that can simultaneously associate with both sites are expected to exhibit enhanced affinity and specificity. We also describe a novel affinitybased high-throughput assay procedure that can be used for PTPase inhibitor screening. The combinatorial library/high-throughput screen protocols furnished a small molecule PTP1B inhibitor that is both potent (K i ‫؍‬ 2.4 nM) and selective (little or no activity against a panel of phosphatases including Yersinia PTPase, SHP1, SHP2, LAR, HePTP, PTP␣, CD45, VHR, MKP3, Cdc25A, Stp1, and PP2C). These results demonstrate that it is possible to acquire potent, yet highly selective inhibitors for individual members of the large PTPase family of enzymes.The initiation, propagation, and termination of signaling events controlling many cellular processes are determined by the level of tyrosine phosphorylation. Phosphotyrosine level, in turn, is maintained in an exquisite balance by the reciprocal activities of protein-tyrosine kinases and protein-tyrosine phosphatases (PTPases).

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“…Members of a class of novel arylbenzonaphthothiophenes and arylbenzonaphthofurans have been developed as PTP1b inhibitors and were shown to improve insulin sensitivity in rodents (Wrobel et al, 1999). One compound from these efforts, ertiprotafib, progressed to phase II clinical trials for treatment of type 2 diabetes.…”

mentioning

confidence: 99%

Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

Erbe¹,

Wang²,

Zhang³

et al. 2004

Mol Pharmacol

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Ertiprotafib belongs to a novel class of insulin sensitizers developed for treatment of type 2 diabetes. In insulin-resistant rodent models, ertiprotafib and a close analog lowered both fasting blood glucose and insulin levels and improved glycemic excursion during an oral glucose tolerance test. In addition, treatment of rodents improved lipid profiles, with significantly lowered triglyceride and free fatty acid levels. These results suggested that this therapeutic activity might involve mechanisms in addition to PTP1b inhibition. In this study, we demonstrate that ertiprotafib activates peroxisome proliferator-activated receptor (PPAR)␣ and PPAR␥ at concentrations comparable with those of known agonists of these regulators.Furthermore, it is able to drive adipocyte differentiation of C3H10T 1/2 cells, a hallmark of PPAR␥ activation. Livers from ertiprotafib-treated animals showed significant induction of acyl-CoA oxidase activity, probably caused by PPAR␣ engagement in these animals. We also show that ertiprotafib inhibits PTP1b in vitro with nonclassic kinetics at concentrations above its EC 50 for PPAR agonism. Thus, the complete mechanism of action for ertiprotafib and related compounds in vivo may involve multiple independent mechanisms, including (but not necessarily limited to) PTP1b inhibition and dual PPAR␣/ PPAR␥ agonism. Ertiprotafib pharmacology and interpretation of clinical results must be seen in light of this complexity.

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PTP1B Inhibition and Antihyperglycemic Activity in the ob/ob Mouse Model of Novel 11-Arylbenzo[b]naphtho[2,3-d]furans and 11-Arylbenzo[b]naphtho[2,3-d]thiophenes

Cited by 121 publications

References 21 publications

Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B

Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B

Acquisition of a Specific and Potent PTP1B Inhibitor from a Novel Combinatorial Library and Screening Procedure

Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

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