Of Protein Tyrosine Phosphatase Inhibitors

N. P. H. M0ller1 ()) • H. S. Andersen2 • C. B. Jeppesen3 • L. F. Iversen4

1 Signal Transduction, Novo Nordisk, Building 9S2.18, 2880 Bagsvsrd, Denmark [email protected]

2 MedChem Research I, Novo Nordisk, Building D9.S.02, 2760 Mal0v, Denmark

3 Molecular Pharmacology, Novo Nordisk, Building C9.S.19, 2760 Mal0v, Denmark

4 Protein Science, Novo Nordisk, Building 6A1.049, 2880 Bagsvsrd, Denmark

1 Introduction 216

2 The Catalytic Machinery 218

3 Bioinformatics 223

4 Structural Requirements for Substrate Specificity 224

5 Identification of Natural Substrates: The Insulin Receptor-Regulating PTP . 225

6 Nature's Regulation of PTP Activity 227

7 PTPs as Drug Targets 229

8 Reversible, Competitive Inhibitors 231

8.1 Challenges 231

8.2 Identification of Chemical Lead Structures 232

8.3 Recommendations and Guidelines 235

9 Structure-Based Design—PTPIB Inhibitors 238

9.1 Peptide-Based Inhibitors—Phosphotyrosyl Mimetics 239

9.2 Non-peptide Inhibitors 242

9.2.1 Phosphorus-Containing Inhibitors 242

9.2.2 Non-phosphorus Inhibitors 243

9.2.3 Simultaneous Optimization Based on Bioinformatics 244

9.2.4 Attraction—Repulsion 245

9.2.5 Steric Fit—Steric Hindrance 246

9.3 Addressing Site 2: Specificity Against TC-PTP 247

10 Bringing It All Together: Future Challenges 250

References 252

Abstract Protein tyrosine phosphatases (PTPs) are a family of intracellular enzymes that remove phosphate from tyrosine phosphorylated proteins. The PTP superfamily includes tyrosine phosphate-specific classical PTPs, dual-specificity PTPs, and low-molecular-weight PTPs. PTPs and protein tyrosine kinases reversibly regulate the phosphotyrosine level in selected cellular proteins, thereby controlling many important signaling pathways in eukaryotes. Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases. As a result, these enzymes have recently attracted much interest as potential drug targets. This is in particular due to the finding that PTP1B knockout mice show increased insulin sensitivity and resistance to diet-induced obesity, thus indicating that PTP1B is an important negative regulator of insulin and leptin action and hence a potentially important drug target for the treatment of diabetes and obesity. The development of PTP inhibitors, in particular PTP1B inhibitors, has been greatly facilitated by an impressive number of X-ray structures that have allowed structure-based design of highly selective inhibitors of PTP1B, the main focus of this review. The initial attempts to design selective PTP inhibitors were based on replacement of pTyr with non-hydrolyzable phosphotyrosyl mimetics in small, efficient PTP peptide substrates, thereby utilizing both the potency and selectivity provided by the amino acid residues. However, several groups have now shown that it is possible to synthesize highly potent and selective non-phosphorus, non-peptide inhibitors of PTP1B. At this point, these achievements to some extent seem to have been reached at the expense of appropriate pharmacokinetic properties, including cellular uptake. Therefore, the next wave within the field of PTP inhibitors is likely to be focused on improvements in this respect. In addition, several other PTPs could potentially be attractive drug targets in autoimmunity and cancer.

Keywords Protein tyrosine phosphatase ■ PTP1B ■ X-ray ■ Bioinformatics ■ Diabetes mellitus ■ Enzyme kinetics

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