Trends in Pharmacological Sciences

The neurovascular unit and combination treatment strategies for stroke.

Publication Date: 2012 May 15 PMID: 22595494
Authors: Zhang, L. - Zhang, Z. G. - Chopp, M.
Journal: Trends Pharmacol Sci

Tissue plasminogen activator (tPA) administered within 4.5h of symptom onset restores cerebral blood flow (CBF) and promotes neurological recovery of stroke patients. However, the narrow therapeutic time window and the risk of intracerebral hemorrhage after tPA treatment pose major hurdles to its clinical usage. In light of the failures of neuroprotective therapies in clinical trials, emerging concepts suggest that neuroprotection alone without restoration of tissue perfusion and vascular integrity may not be adequate for treatment of acute stroke. Here we review evidence of the use of adjuvant pharmacological agents to extend the therapeutic window for tPA via targeting the neurovascular unit and the underlying mechanisms of the combination therapy in experimental stroke.

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Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease.

Publication Date: 2012 May 9 PMID: 22578536
Authors: Lee, B. D. - Dawson, V. L. - Dawson, T. M.
Journal: Trends Pharmacol Sci

Parkinson's disease (PD) is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra. Although the etiology for most PD remains elusive, the identification of specific genetic defects in familial cases of PD and the signaling pathways governed by these genes has provided tremendous insight into PD pathogenesis. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequently found in familial and sporadic PD. Although current knowledge regarding the regulatory mechanisms of LRRK2 activation is limited, it is becoming increasingly evident that aberrant kinase activity of the pathologic mutants of LRRK2 is associated with neurodegeneration, suggesting that the kinase activity of LRRK2 is a potential therapeutic target. In addition, LRRK2 inhibitors might provide valuable tools to understand the pathophysiological and physiological roles of LRRK2 as well as the etiology of PD. We discuss here the potential and feasibility of targeting LRRK2 as a therapeutic strategy for PD.

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GPR119 as a fat sensor.

Publication Date: 2012 May 2 PMID: 22560300
Authors: Hansen, H. S. - Rosenkilde, M. M. - Holst, J. J. - Schwartz, T. W.
Journal: Trends Pharmacol Sci

The GPR119 receptor is expressed predominantly in pancreatic beta cells and in enteroendocrine cells. It is a major target for the development of anti-diabetic drugs that through GPR119 activation may stimulate both insulin and GLP-1 release. GPR119 can be activated by oleoylethanolamide and several other endogenous lipids containing oleic acid: these include N-oleoyl-dopamine, 1-oleoyl-lysophosphatidylcholine, generated in the tissue, and 2-oleoyl glycerol generated in the gut lumen. Thus, the well-known stimulation of GLP-1 release by dietary fat is probably not only mediated by free fatty acids acting through, for example, GPR40, but is also probably mediated in large part through the luminal formation of 2-monoacylglycerol acting on the 'fat sensor' GPR119. In the pancreas GPR119 may also be stimulated by 2-monoacylglycerol generated from local turnover of pancreatic triacylglycerol. Knowledge about the endogenous physiological ligands and their mode of interaction with GPR119 will be crucial for the development of efficient second-generation modulators of this important drug target.

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Drug-mediated toxicity: illuminating the 'bad' in the test tube by means of cellular assays?

Publication Date: 2012 May 1 PMID: 22554615
Authors: Tralau, T. - Luch, A.
Journal: Trends Pharmacol Sci

Health problems are rising worldwide, be it as a consequence of lifestyle and longevity in increasingly affluent societies or due to a sharp rise in bacterial antibiotic resistance. The pharmaceutical industry is caught between high rates of attrition and the rather slow pace of a historically large regulatory system for pharmacological safety. Meanwhile, the past decade has seen a tremendous evolution of the biological toolbox, most notably of cellular assays, stem-cell differentiation and organ-mimicking systems. These systems were readily adapted for lead-compound identification. However, their use as toxicological test systems is lagging behind, not least because of a lack of regulatory acceptance. This review tries to elucidate the scale of the problem and discusses the applicability of the assays currently available, with particular regard to the use of stem cells.

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Liver X receptor biology and pharmacology: new pathways, challenges and opportunities.

Publication Date: 2012 Apr 26 PMID: 22541735
Authors: Jakobsson, T. - Treuter, E. - Gustafsson, J. A. - Steffensen, K. R.
Journal: Trends Pharmacol Sci

Nuclear receptors (NRs) are master regulators of transcriptional programs that integrate the homeostatic control of almost all biological processes. Their direct mode of ligand regulation and genome interaction is at the core of modern pharmacology. The two liver X receptors LXRalpha and LXRbeta are among the emerging newer drug targets within the NR family. LXRs are best known as nuclear oxysterol receptors and physiological regulators of lipid and cholesterol metabolism that also act in an anti-inflammatory way. Because LXRs control diverse pathways in development, reproduction, metabolism, immunity and inflammation, they have potential as therapeutic targets for diseases as diverse as lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Recent insights into LXR signaling suggest future targeting strategies aiming at increasing LXR subtype and pathway selectivity. This review discusses the current status of our understanding of LXR biology and pharmacology, with an emphasis on the molecular aspects of LXR signaling that constitute the potential of LXRs as drug targets.

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Discovery of boceprevir, a direct-acting NS3/4A protease inhibitor for treatment of chronic hepatitis C infections.

Publication Date: 2012 May PMID: 22521415
Authors: Venkatraman, S.
Journal: Trends Pharmacol Sci

Hepatitis C virus (HCV) infection is the primary cause of liver cirrhosis and hepatocellular carcinoma. HCV is the leading cause of liver transplantation in the USA, and more than 200 million people worldwide are infected with HCV. Before the introduction of NS3 protease inhibitors, the standard of care was treatment with peg-interferon and ribavirin. Recent developments in virology have identified many novel targets in the HCV genome, allowing the development of direct-acting antivirals. In this article, I outline the discovery and development of boceprevir, the first HCV NS3/4A protease inhibitor approved for treatment of genotype 1 HCV infection. Boceprevir greatly improves the sustained virologic response (SVR) and provides new hope for treating genotype 1 infections.

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Rapid-access, high-throughput synchrotron crystallography for drug discovery.

Publication Date: 2012 May PMID: 22521107
Authors: Wasserman, S. R. - Koss, J. W. - Sojitra, S. T. - Morisco, L. L. - Burley, S. K.
Journal: Trends Pharmacol Sci

Synchrotron X-ray sources provide the highest quality crystallographic data for structure-guided drug design. In general, industrial utilization of such sources has been intermittent and occasionally limited. The Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline provides a unique alternative to traditional synchrotron use by pharmaceutical and biotechnology companies. Crystallographic experiments at LRL-CAT and the results therefrom are integrated directly into the drug discovery process, permitting structural data, including screening of fragment libraries, to be routinely and rapidly used on a daily basis as part of pharmaceutical lead discovery and optimization. Here we describe how LRL-CAT acquires and disseminates the results from protein crystallography to maximize their impact on the development of new potential medicines.

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Structure-based drug screening for G-protein-coupled receptors.

Publication Date: 2012 May PMID: 22503476
Authors: Shoichet, B. K. - Kobilka, B. K.
Journal: Trends Pharmacol Sci

G-protein-coupled receptors (GPCRs) represent a large family of signaling proteins that includes many therapeutic targets; however, progress in identifying new small molecule drugs has been disappointing. The past 4 years have seen remarkable progress in the structural biology of GPCRs, raising the possibility of applying structure-based approaches to GPCR drug discovery efforts. Of the various structure-based approaches that have been applied to soluble protein targets, such as proteases and kinases, in silico docking is among the most ready applicable to GPCRs. Early studies suggest that GPCR binding pockets are well suited to docking, and docking screens have identified potent and novel compounds for these targets. This review will focus on the current state of in silico docking for GPCRs.

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Advances in structure-based drug design.

Publication Date: 2012 May PMID: 22503451
Authors: Schaffhausen, J.
Journal: Trends Pharmacol Sci

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Structural biology and drug discovery for protein-protein interactions.

Publication Date: 2012 May PMID: 22503442
Authors: Jubb, H. - Higueruelo, A. P. - Winter, A. - Blundell, T. L.
Journal: Trends Pharmacol Sci

Although targeting protein-protein interfaces of regulatory multiprotein complexes has become a significant focus in drug discovery, it continues to pose major challenges. Most interfaces would be classed as 'undruggable' by conventional analyses, as they tend to be large, flat and featureless. Over the past decade, encouragement has come from the discovery of hotspots that contribute much of the free energy of interaction, and this has led to the development of tethering methods that target small molecules to these sites, often inducing adaptive changes. Equally important has been the recognition that many protein-protein interactions involve a continuous epitope of one partner and a well-defined groove or series of specific small pockets. These observations have stimulated the development of stapled alpha-helical peptides and other proteomimetic approaches. They have also led to the realisation that fragments might gain low-affinity 'footholds' on some protein-protein interfaces, and that these fragments might be elaborated to useful modulators of the interactions.

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Structural approaches to obtain kinase selectivity.

Publication Date: 2012 May PMID: 22503441
Authors: Norman, R. A. - Toader, D. - Ferguson, A. D.
Journal: Trends Pharmacol Sci

One of the grand challenges in kinase drug discovery is the design of small-molecule inhibitors with selectivity profiles that will ultimately be efficacious in the clinic. Current medicinal chemistry strategies make heavy use of structural, biophysical and computational approaches to achieve this multi-faceted goal. Here we review structure-based approaches underlying the development of several molecules that are currently in clinical trials, including the cMet inhibitor ARQ197 and the Bcr-Abl inhibitor ponatinib. We highlight the challenge posed by the emergence of resistance mutants and discuss promising lead generation strategies to obtain selective inhibitors of protein and lipid kinases such as targeting of specific sites, the use of fragment-based approaches and new chemical probes based on metal complexes.

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The role of structural information in the discovery of direct thrombin and factor Xa inhibitors.

Publication Date: 2012 May PMID: 22503439
Authors: Nar, H.
Journal: Trends Pharmacol Sci

The quest for novel medications to treat thromboembolic disorders such as venous thrombosis, pulmonary embolism and stroke received a boost when the 3D structures of two major players in the blood coagulation cascade were determined in 1989 and 1993. Structure-guided design of inhibitors of thrombin (factor IIa, fIIa) and factor Xa (fXa) eventually led to the discovery of potent, selective, efficacious, orally active and safe compounds that proved successful in clinical studies. In 2008, the direct thrombin inhibitor dabigatran etexilate developed by Boehringer Ingelheim became the first novel antithrombotic molecular entity to enter the market in 50 years. Additional compounds targeting factor Xa were subsequently granted marketing authorization or are in late-stage clinical studies. In this review, I use selected case studies to describe the discovery of novel fIIa and fXa inhibitors, with a particular emphasis on the pre-eminent role that structural information played in this process.

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Iminoheterocycle as a druggable motif: BACE1 inhibitors and beyond.

Publication Date: 2012 May PMID: 22480948
Authors: Zhu, Z.
Journal: Trends Pharmacol Sci

Beta-secretase 1 (BACE1) is a central nervous system (CNS) aspartyl protease required for production of amyloid beta (Abeta) peptides. Brain-penetrant BACE1 inhibitors are central to test the 'amyloid hypothesis', which suggests that a reduction of Abeta species in the CNS would halt or even reverse Alzheimer's disease. Discovery of the iminoheterocycle class of BACE1 inhibitors (which show robust efficacy in reduction of CNS Abeta species in animal models) marked an important milestone. These discoveries arose independently from multiple research laboratories that took different paths to end at the same scaffolds. These druggable motifs should be applicable to other aspartyl proteases of therapeutic importance and also to other protein targets involving crucial interactions with carboxylic acid side chains. Here, a comparison of these approaches to BACE1 discovery will showcase how it is important to pay attention to the intrinsic physicochemical properties of the lead series, even at the very early stage of drug discovery.

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New insights from structural biology into the druggability of G protein-coupled receptors.

Publication Date: 2012 May PMID: 22465153
Authors: Mason, J. S. - Bortolato, A. - Congreve, M. - Marshall, F. H.
Journal: Trends Pharmacol Sci

The recent availability of X-ray structures for diverse ligand-bound Family A G protein-coupled receptors (GPCRs) in multiple conformations (inactive form with an antagonist/inverse agonist bound and active form with an agonist bound) now enables rational drug design efforts that have historically been applied to soluble enzyme targets. Here, we review properties of these GPCR binding sites, using a unique combination of calculated physicochemical properties and water energetics (GRID, WaterMap and SZMAP) to provide a new perspective and rational assessment of druggability for each GPCR target binding site. Examples are described from several well-studied enzyme systems to support this advanced structure-based approach to assessing druggability and to contrast their properties with those of GPCRs. Changes in receptor conformations between the GPCR inactive and active forms evident from the protein structures are discussed, yielding important pointers for rational drug design of antagonists and agonists and a better understanding of GPCR activation.

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Experiences in fragment-based drug discovery.

Publication Date: 2012 May PMID: 22459076
Authors: Murray, C. W. - Verdonk, M. L. - Rees, D. C.
Journal: Trends Pharmacol Sci

Fragment-based drug discovery (FBDD) has become established in both industry and academia as an alternative approach to high-throughput screening for the generation of chemical leads for drug targets. In FBDD, specialised detection methods are used to identify small chemical compounds (fragments) that bind to the drug target, and structural biology is usually employed to establish their binding mode and to facilitate their optimisation. In this article, we present three recent and successful case histories in FBDD. We then re-examine the key concepts and challenges of FBDD with particular emphasis on recent literature and our own experience from a substantial number of FBDD applications. Our opinion is that careful application of FBDD is living up to its promise of delivering high quality leads with good physical properties and that in future many drug molecules will be derived from fragment-based approaches.

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