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Phosphatases: Emerging Role in Signal Transduction, Human Therapeutics, & As Drug Targets
Drug and Market Development Publishing, Feb 2004
The purpose of this report is to introduce the enzyme class known as phosphatases and todescribe why they are an upcoming class of targets for drug discovery and development. Several hundred protein targets have been identified and characterized to date as appropriate subjects for developing small molecule therapeutics. These targets include several protein classes (Kinases, GPCRs, Growth Factor Receptors, Transcription Factors) that have been identified, cloned, sequenced, and studied for their function in normal cells and in disease cells. Dysregulation of these protein targets in disease cells leads to altered phenotype expression. It has been speculated that there may be thousands of druggable protein targets but that only a fraction have been identified and validated to date. Some of the most popular drug targets include:- G protein coupled receptors (GPCR).- Growth factor receptors- Histone deacetylase- Kinases- Transcription factors- ProteosomeAdvancement in several areas of technologies (including genomics and proteomics) and the completion of the human genome sequencing project is credited for the growth of therapeutic target collection. The functional characterization and validation of these targets is extremely important and has prioritized certain targets as appropriate for small molecule discovery and development. Among these more promising targets are the phosphatases. Phosphatases are enzymes that catalyze the removal of phosphate groups that are added on to molecules by another catalytic protein, a specific kinase. It is now becoming evident that like kinases, phosphatases also are sequence specific in their enzymatic action. The sequencing of the human genome and classification by sequence homology into druggable targets has illustrated that phosphatases make up 4% of the total number of potential known targets.Since their initial identification and characterization, phosphatases are now considered critical targets and are being pursued by several major pharmaceutical companies such as Vertex, Sunesis, Ceptyr, Abbott, and others. The increasing recognition of phosphatases as a druggable target has been aided recently through a better understanding of their role in the cellular signal transduction mechanism.The role of specific phosphatases has now been well defined and characterized in diseases such as obesity, diabetes, and cancer. Intense focus on phosphatases as drug development targets in diabetes has been due to functional characterization and in-depth analysis of insulin-signaling pathway. The number of reports published to date in the area of phosphatases is approximately 85,254. Conversely, over 250,000 reports are published in the area of kinases. This clearly indicates the tremendous effort directed toward the understanding and characterization of kinases as compared to phosphatases as drug discovery and development targets.The signal transduction pathways within cells are mediated by several molecular events such as ligand/receptor interactions, phosphorylation of downstream proteins, micro-localization, protein-protein interaction, and DNA protein interaction. The key events in signal transduction pathways are the phosphorylation of several membrane proteins including growth factor receptors, proteins in the cytosol, and proteins in the nucleus. Enzymes that carry out such key phosphorylation events are called kinases.There are several different kinds of kinases that are substrate sequence dependent. It is thought that 35% of all cellular proteins are subjected to phosphorylation at one or more amino acid residues. Eukaryotic cells are estimated to possess 575 kinase genes equivalent to 22% of the genome. Virtually every disease has at its core a deficiency or excess of proteins in signal transduction pathways that can be negatively regulated by phosphatases and can remove the phosphate added by a specific kinase. It is critical to note that the functional state of a protein is determined by a sensitive balance between the actions of kinases and phosphatases. This makes both enzymes equally important in cellular regulation. Understanding the role of protein phosphatases in human diseases has lagged considerably behind that of protein kinases. This is essentially due to slow discovery and development of reagents that can differentiate between the several different kinds of phosphatases that have been identified and characterized to date .With the knowledge generated by the “omics” revolution and availability of transgenic models, it is widely acknowledged that the regulation of protein phosphorylation requires the coordinated control of both kinases and phophatases. Regulation of phosphatases is considered as delicate and elegant as that of kinases. As alluded to above, several big and small pharmaceutical companies have established small molecule development programs against specific phosphatases. This list is small but is expected to grow as more phosphatases are identified, sequenced, characterized, and validated for their role in specific signal transduction pathways and their diseases associations. In this report we provide an in-depth analysis of phosphatases, their entry into the drug discovery arena, and their role in human diseases.
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