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Protein tyrosine phosphatase 1B inhibitors for diabetes

Nature Reviews Drug Discovery volume 1, pages 696709 (2002) | Download Citation

Subjects

Abstract

Increased incidence of type 2 diabetes mellitus and obesity has elevated the medical need for new agents to treat these disease states. Resistance to the hormones insulin and leptin are hallmarks of both type 2 diabetes and obesity. Drugs that can ameliorate this resistance should be effective in treating type 2 diabetes and possibly obesity. Protein tyrosine phosphatase 1B (PTP1B) is thought to function as a negative regulator of insulin and leptin signal transduction. This article reviews PTP1B as a novel target for type 2 diabetes, and looks at the challenges in developing small-molecule inhibitors of this phosphatase.

Key points

  • Obesity and type 2 diabetes have become epidemic medical problems and will cause significant morbidity and mortality if new therapeutic agents cannot be brought forward.

  • Protein tyrosine phosphatase 1B (PTP1B) has been shown to be involved in the negative regulation of both insulin and leptin action at the in vitro, ex vivo and in vivo levels. A growing body of human genetic data also support the hypothesis that PTP1B has an important role in insulin signalling and possibly in obesity in humans.

  • PTP1B has been implicated in diabetes and obesity in knockout-mouse studies on a normal background. When crossed onto ob/ob mice, improvement in blood glucose and obesity is seen. When Ptp1b antisense oligonucleotides are administered in vivo to ob/ob mice, normalized blood glucose levels are obtained. Insulin sensitivity is improved at the cellular level.

  • PTP1B is tractable to structure-based drug design, and the crystal structure is well known. Recently, the crystal structure of the closely related T-cell protein tyrosine phosphatase (TCPTP) has become available, raising the possibility for designing selective inhibitors.

  • Potent (Ki values in the nM range) inhibitors of PTP1B are known, and oxamic acids are a common structural motif found in these compounds. The high polar surface area (PSA) and charge of this functionality make further optimization difficult, and an intense search to uncover phosphotyrosine mimetics with improved physico-chemical properties is in progress.

  • Pro-drugs of the oxamic acids and replacement of the acid functionality with isosteric functional groups might provide compounds with improved physico-chemical properties.

  • Lipophilic compounds have been reported — one of the two reported structures seems to be a competitive inhibitor of PTP1B and the other does not. This highlights the need for a clear understanding of the mechanism of inhibition and an understanding of the kinetics of compounds.

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Acknowledgements

We apologize to colleagues for the many references we could not site due to space limitations. We thank A. Castro for collecting some of the data and J. Thomson, D. Vanderpool and J. Nelson for reading the manuscript.

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  1. Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.

    • Theodore O. Johnson
    • , Jacques Ermolieff
    •  & Michael R. Jirousek

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Correspondence to Michael R. Jirousek.

Glossary

OBESITY

In the United States, obesity is defined as having a body-mass index (BMI; the weight in kg divided by the height (in m) squared) ≥ 30 or BMI ≥ 27 with diabetes, hypertension or dyslipidaemia.

PANCREATIC ISLET

Islets of Langerhans, which are found in the pancreas, consist of insulin-producing β-cells, somatostatin-producing δ-cells, glucagon-producing α-cells and polypeptide-producing pp cells.

POSTPRANDIAL

The period of macronutrient absorption after a meal, usually considered to be two hours in length.

METABOLIC SYNDROME

The appearance of several metabolic disorders together. The World Health Organisation defines this as one of type 2 diabetes, impaired glucose tolerance or insulin resistance, in combination with two of the following presentations — hypertension, obesity, hypertriglyceridaemia or low HDL, or microalbuminuria.

GLUCOSE HOMEOSTASIS

The maintenance of glucose levels during fluctuating physiological pressures, such as eating, exercising, resting or disease.

PROTEIN TYROSINE PHOSPHATASE

An enzyme that removes phosphate from tyrosine residues in proteins.

OMENTAL FAT

Adipose tissue located in the omental, such as the viscera below the subcutaneous space.

OJI–CREE INDIANS

A Native North American tribe that lives in the Sandy Lake area of Canada. This population has an incidence of obesity-related type 2 diabetes or impaired glucose tolerance of 40%.

SINGLE-NUCLEOTIDE POLYMORPHISM

(SNP). A variation in a nucleotide in a gene that could result in altered gene function or altered protein function if it affects amino-acid coding.

LINKAGE DISEQUILIBRIUM

The association between a pair of alleles at closely linked loci that induces haplotype frequencies different than the product of the individual allele frequencies.

HDL CHOLESTEROL

High-density lipoprotein (HDL) that is associated with a high proportion of protein (48%) and low triglyceride (3%) and cholesterol (19%) — HDL density is 1.06–1.21 g ml−1.

ob/ob MOUSE

A homozygous mutation in the leptin gene located on chromosome 6 that causes the absence of functional leptin in the mouse strain C57BL/6J, producing a model of severe obesity with hyperphagia and diabetes.

ARYL PHOSPHATE

The phosphate group attached at the 4-position of the phenyl group in tyrosine.

NUCLEOPHILE

An atom that is attracted to the nucleus of another — in this case, the cysteine sulphur acts as a nucleophile and attacks the phosphotyrosine phosphorous atom.

HYDROPHOBIC

A molecular interaction that occurs in the absence of aqueous solvent or water.

SALT BRIDGE

The formation of an ionic-charge interaction between two molecules or between two regions of a molecule.

PEPTIDOMIMETIC

Mimicking a peptide–peptide interaction through a non-peptide bond or structure.

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