Drug discovery using signal transduction

The molecular details of how a cell responds to its environment was analysed in detail only in the mid 1970’s. Bacteria were considered earlier for testing and showed that signal transduction concentrated on macro responses such as chemotaxis. The study also revealed that the bacterial chemotaxis was proportional to the amount of the receptor present on the cell surface. Later the research conducted on cancer transformation also showed a specific class of enzyme known as kinases which undergoes phosphorylation with other protein at specific amino acid residue tyrosine and ultimately establishes the signal transduction pathway leading to the disease.

The cellular signalling also called signal transduction refers to a cascade process that converts an extracellular stimulus into an intracellular response to make the cell adapt to a changing environment. The signal transduction will detect the changes that are taking from the outside region and communicate these events to the interior region of the cells. The signal transduction describes the process of converting external signals like hormones, growth factors, neurotransmitters and cytokines to a specific internal cellular response such as gene expression, cell division or even cell suicide. This process keeps all the cells working as a team.

The signal transduction controls cellular events that range from the normal growth and development to the onset and invasion of diseases. The signal transduction if maintained in good order result in a healthy cell. If the signal transduction process lacks an individual link in the chain reaction will lead to a disease state. In the present scenario progress has been made in signal transduction correlating them with the disease to identify novel drug target. The companies developing the target drug using signal transduction faces two major constraints, one-  the pathways are still not completely understood and second is the key pathway components suspected to participate in the disease have to be validated as potential drug target. There are thousands of cellular pathway making it a prime targets for basic research and medicines.

Much of the signal transduction research today revolves around kinases, as these proteins add phosphate group to a target protein and initiate the kinase mediated signalling cascades. The kinases are reported to be involved in a plethora of diseases. Nearly 20-25% of the druggable genome consists of kinases involved in signal transduction. There are only six kinase inhibitors currently available in the clinical practise. This indicates that many more development is yet to be exploited in this area.

The external information through stimuli or signals is collected by the cell surface receptors membrane-bound proteins, such as G protein-coupled tyrosine-kinase and ion-channel receptors. The process starts at the cell membrane, were an external stimuli will initiate a cascade of enzymatic reactions inside the cell (Fig-1). The enzymatic reactions include phosphorylation of proteins as mediators of down stream process. The receptors that constitute the channels allow the movement of signals to pass in the form of small ion either into or outside the cell when it interacts with ligand. The movement of ions create a change in electrical potential of the cell, which in turn propagates the signal along the cells. The ligand-receptor interaction to many intracellular events is seen with more complex signal transduction process. The intracellular events include tyrosine kinases and /or serine/threonine kinases. The outcome of these cellular events leads to alteration in cellular activity and changes in the gene expression within the responding cells.

The signalling disorders reveal a major cause for the pathological conditions. The recently identified validated target molecules for the treatment of cancer and in infectious disease are signal transduction related macromolecules. The identified targets are mostly kinases. The cellular functions rely on the highly coupled intercellular networks of specific protein-protein interactions. These interactions are in turn functionally controlled by reversible phosphorylation reaction catalyzed by protein kinases.

The signal transduction receptors are grouped into three general classes-  receptors that penetrate the plasma membrane and have intrinsic enzymatic activity, the receptors that are coupled inside the cell to GTP-binding and hydrolyzing proteins (termed G-protein) and finally receptors that are found intracellulary and upon ligand binding migrate to the nucleus where the ligand-receptor complex directly affects gene transcription.

A signal peptide TT-232, a structural somatostatin was developed and has reached Phase II clinical trial against melanoma. The experiment with TT-232 also revealed that there was a strong anti-inflammatory activity. The host cell signal inhibition, a novel approach for treating infectious diseases was initiated by inhibition of the essential signals required at the host cell level for the survival of the pathogen with kinase inhibitors. The method has found application in the inhibition of various infectious diseases.

The kinaTor technology provides selectivity panel for the optimization on distinct kinase target. In case of the privileged structure-based inhibitor design the kinaTor technology help to identify novel kinase targets for an investigated compound. The antibodies for the study of individual phosphorylation sites on many tyrosine kinases receptor like EGFR,ErbB2,c-MET, c-Kit, PDGFR, Insulin/IGFIR etc are used for understanding the signalling pathway for the  development of new tools to know the regulation of these receptors.

The study with VEGF or vascular endothelial growth factors revealed that these receptors have tyrosine kinase activity and if blocked could prove to prevent the growth of tumour. The research based on signal transduction has developed an integrated kit to analyse the activity of protein in the disease process. A dual selective inhibitors of both src and Ab1, were Ab1 is a key target for the treatment of leukaemia. The inhibition of p38 MAPK, which regulates intracellular signalling pathways in response to environmental stress can block the production of inflammation causing cytokines like IL-1ß and TNF-a and are effective against arthritis and bone resorption in animal model. The compounds SU5416 and SU6668 have entered in various stages of clinical trial for the treatment of colorectal cancer, solid tumours and kaposis sarcoma.  The Fas receptor (FasR, CD95, ApO-1) and its ligand (FasL) can be used against transplant rejection and T cell-mediated inflammatory diseases. The consumption of genistein a natural product from soyabean, having protein-tyrosine kinase inhibitor has shown to reduce the incidence of metastatic prostate cancer.

The antisenense oligonucleotides which can selectively reduce target gene expression can be used as a potential for therapeutic target. The existence of growth  factor signalling pathways, which has an impact on different RNA processing events have open new avenues in investigation and disease understanding at the level of  RNA-targeted signalling. The role of neuronal signalling in Alzheimers disease has attracted an intense interest in signalling molecules to coordinate appropriate cellular responses that allow an exploration of upstream and down stream events to understand the disease mechanism for the future development of drug target. The therapeutic agents modulating the AngII- mediated signal transduction are effective in congestive heart failure. The alkylphocholines inhibit phospholipase C and protein kinase which play a major role in intracellular signalling pathways are used as anticancer agents. The drug molecules acting on specific proteins of signal transduction cascade are called signal transduction modulators (STM). The two anticancer drugs trastuzumab and imatinib coming under STM have received world wide regulatory approval in several cancer conditions.