CAMBRIDGE, U.K., June 12, 2003 (PRIMEZONE) -- Astex Technology, the fragment-based drug discovery company, today announced that its scientists have made a major discovery relating to a key protein implicated in diabetes and obesity. The work describes a novel form of Protein Tyrosine Phosphatase 1B (PTP1B) and is reported in the latest edition of the leading science journal Nature (1). Astex scientists used the Company's proprietary structural biology technologies to determine the three-dimensional shape of a novel form of PTP1B that may have major implications for its biological function and role in disease.
Inhibiting PTP1B has been the focus of intense pharmaceutical research in the discovery and development of novel drugs to treat diabetes and obesity. PTP1B is thought to mediate diabetes and weight gain. The combined worldwide market for drugs to treat diabetes and obesity is already in excess of $5 billion. Despite intense research efforts, novel drug candidates targeting PTP1B have remained elusive.
"Most pharmaceutical and biotechnology companies have struggled in their search for promising drug candidates to inhibit PTP1B. We believe our discoveries may explain the reasons for these failures and also identify novel strategies for targeting this key protein. This is another example of our fragment-based drug discovery approaches succeeding against disease targets that are of high value for pharmaceutical companies," said Dr. Harren Jhoti, Chief Scientific Officer and Co-founder of Astex. The Company is now engaged in exploiting these discoveries, which are the subject of patent filings, to identify novel small molecule therapeutics for the treatment of diabetes and obesity.
Astex is a fragment-based drug discovery company pioneering the use of high-throughput X-ray crystallography for the rapid identification of novel drug candidates. The Company's unique fragment-based drug discovery approach, termed Pyramida, utilizes protein crystal structures to detect the binding of drug fragments, which are then optimized into potent lead compounds. Facilitating this approach is Astex's integrated drug discovery platform, which covers all aspects of structure-based drug discovery including protein production, crystallization, structure determination, bioinformatics, computational and medicinal chemistry and biology and DMPK.
Astex is focusing its drug discovery approaches on proprietary and public domain protein targets from families and/or pathways. This includes validated kinases, phosphatases and proteases implicated in human disease. Astex has drug discovery collaborations with Schering AG, AstraZeneca, Mitsubishi Pharma and with the Institute of Cancer Research, UK and Cancer Research Technology, has further research agreements with another large pharmaceutical company, and has structural biology research agreements with AstraZeneca, Aventis Pharmaceuticals and Mitsubishi Pharma focused on solving novel cytochrome P450 crystal structures.
Editors Notes:
Protein tyrosine phosphatases are a family of proteins that regulate signal transduction pathways in cells and have been implicated in the development of cancer, diabetes, rheumatoid arthritis and hypertension. Protein Tyrosine Phosphatase 1B (PTP1B) is involved in insulin resistance through its role in the dephosphorylation of the insulin receptor (IR), which in turn is a prime factor leading to type 2 diabetes. PTP1B activity is known to be significantly greater in insulin-resistant human tissue and in animal models of diabetes. Over-expressing PTP1B in cell lines has been found to decrease the response to insulin while PTP1B knockout mice are found to be resistant to weight gain and remain insulin sensitive on a high-fat diet. On the basis of such biochemical and cellular studies and the pivotal study with knockout mice, PTP1B is viewed as one of the most promising emerging targets for type 2 diabetes.
Astex's paper describes a novel form of PTP1B that is thought to play a role in the regulation of this enzyme whose biological function is to control the activity of the insulin receptor. This novel form includes a sulphenyl-amide group in the active site of the protein, a feature not previously observed in any other proteins. The sulphenyl-amide group in PTP1B radically alters the architecture of the active site and can be exploited in novel strategies for drug design.
(1) Rob L. van Montfort, Miles Congreve, Dominic Tisi, Robin Carr & Harren Jhoti, "Oxidative state of the active-site cysteine in protein tyrosine phosphatase 1B", Nature, 12 June 2003, 423, 773-777