Recent Advances In Drug Discovery Research Articles

Targeting Signal Transducer and Activator of Transcription Signaling Pathway in Leukemias

Signal transducer and activator of transcription (STAT) proteins comprise a seven-member family of latent cytoplasmic transcription factors that are activated through tyrosine phosphorylation by a variety of cytokines and growth factors. Aberrant activation of STATs accompanies malignant cellular transformation with resultant leukemogenesis. Constitutive activation of STATs has been demonstrated in various leukemias. A better understanding of the mechanisms of dysregulation of the STAT pathway and understanding of the cause and effect relationship in leukemogenesis may serve as a basis for designing novel therapeutic strategies directed against STATs. Mechanisms of STAT activation, the potential role of STAT signaling in leukemogenesis, and recent advances in drug discovery targeting the STAT pathway are the focus of this review.

Cardiovascular Effects of Modulators of Soluble Guanylyl Cyclase Activity

Soluble guanylyl cyclase (sGC) is one of the key enzymes of the nitric-oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. Located in virtually all mammalian cells, it controls the vessel tone, smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In vivo sGC activity is mainly regulated by NO which in turn is released from L-arginine by nitric oxide synthases. One of the main diseases of the cardiovascular system, endothelial dysfunction, leads to a diminished NO synthesis and thus increases vessel tone as well as the risk of thrombosis. The predominant therapeutic approach to this condition is a NO replacement therapy, as exemplified by organic nitrates, molsidomin, and other NO releasing substances. Recent advances in drug discovery provided a variety of other approaches to activate sGC, which may help to circumvent both the tolerance problem and some non-specific actions associated with NO donor drugs. Substances like BAY 41-2272 stimulate sGC in a heme-dependent fashion and synergize with NO, allowing to enhance the effects both of endogenous NO and of exogenous NO donors. On the other hand, heme-independent activators like BAY 58-2667 allow to activate sGC even if it is rendered unresponsive to NO due to oxidative stress or heme loss. Furthermore, a few substances have been described as specific inhibitors of sGC that allow to alleviate the effects of excess NO production as seen in shock. This review discusses the cardiovascular effects of heme-dependent and heme-independent activators as well as of inhibitors of sGC.

Introduction: Advancing Drug Discovery for Alzheimers Disease [ ISOA Fifth Annual Investigators Meeting “Recent Advances in Drug Discovery and Development for Alzheimers Disease” Sponsored by Elan Pharmaceuticals Inc, The Graphic Expression, Glaxo Smith Kline Pharmaceuticals, Neurochem Inc, Pfizer Inc. (Guest Editors: Howard M. Fillit and Lorenzo M. Refolo)

Introduction: Advancing Drug Discovery for Alzheimers Disease [ ISOA Fifth Annual Investigators Meeting “Recent Advances in Drug Discovery and Development for Alzheimers Disease” Sponsored by Elan Pharmaceuticals Inc, The Graphic Expression, Glaxo Smith Kline Pharmaceuticals, Neurochem Inc, Pfizer Inc. (Guest Editors: Howard M. Fillit and Lorenzo M. Refolo)

Targeting C5a: Recent Advances in Drug Discovery

Activation of complement via the innate and adaptive immune system is vital to the body's defences in fighting infections. Unregulated complement activation is likely to play a crucial role in the pathogenesis of several diseases including psoriasis, adult (acute) respiratory distress syndrome (ARDS), bullous pemphigoid (BP), rheumatoid arthritis (RA) and ischemia-reperfusion (I/R) injury. The 74 amino acid peptide C5a is released after complement activation at sites of inflammation and is a potent chemoattractant for neutrophils, basophils, eosinophils, leukocytes, monocytes and macrophages. Recombinant proteins and humanized anti-C5 antibodies have been recently developed for blocking specific proteins of the complement system bringing renewed attention towards complement inhibition. Pharmacological studies have been highlighting the complement fragment C5a as an interesting target for the management of complement mediated diseases. Specific inhibition of C5a biological activity could gain therapeutic benefit without affecting the protective immune response. In the last few years several peptide and non-peptide antagonists of C5a have been discovered and tested in relevant pharmacological models; the availability of orally active compounds is rapidly helping to delineate the precise role of C5a in immunoinflammatory disorders. Moreover, mutagenesis data for the C5a/C5a receptor (C5aR) couple make C5aR a valuable model for mechanistic studies of peptidergic G-protein coupled receptors (GPCRs). The aim of this review is to outline the recent advances in C5a inhibition, especially highlighting the value of a multidisciplinary integrated approach in drug discovery.

Small Molecule Antagonists Targeting Growth Factors/Receptors

Abstract: Control of cell proliferation is regulated by interaction of soluble growth factors and cell membrane receptors. Studies of growth factors and their receptors provide a new approach to elucidate mechanisms of cancer progression, and more importantly, a unique potential for development of targeted anticancer therapy. A growth factor (ligand) binding to its receptor(s) triggers a complex series of intracellular signaling pathways th_at may culminate in a change in cell behavior. Considerable number of studies indicate that the inappropriate expression and/or activation of the growth factor/receptors can mediate abnormal cellular signaling and oncogenic transformation both in vitro and in vivo system. These results strongly support the hypothesis that growth factors/receptors plays an important role in the tumorigenesis of cancer. A number of families of structurally related growth factors and receptors have been identified and were considered as potential targets for specific antitumor therapy. This review will focus on recent advances in drug discovery that have identified small organic molecules that affect ligand binding, kinase activity, and signaling transduction and alter cell function. Recent progress of small molecule-based drug discovery targeting several growth factor/receptor families is presented. Approach utilizing computer based 3D pharmacophore searches is discussed. These approaches to develop novel anticancer therapies focus on mechanisms different from conventional chemotherapeutic and radiotherapeutic regimens. These targeted anticancer therapies may be highly tumor cell specific, since they do not require host accessory factors. Furthermore, these potential small molecule drugs may have the capacity to synergistically or additively improve the presently available hormonal, radiation or chemotherapy of cancer.