Current Medicinal Chemistry (v.16, #8)

PI3K Inhibitors for Cancer Therapy: What has been Achieved So Far? by Peng Wu, Tao Liu, Yongzhou Hu (916-930).
PI3K is a large duel lipid and protein kinase that catalyzes phosphorylation of the 3-hydroxyl position of phosphatidylinositides (PIs) and plays a crucial role in the cellular signaling network. Inhibition of the phosphatidylinositol 3- kinase (PI3K) signaling pathway is a newly identified strategy for the discovery and development of certain therapeutic agents. Among the various subtypes of PI3K, class IA PI3Kand#945; has gained increasing attention as a promising drug target for the treatment of cancer due to its frequent mutations and amplifications in various human cancers. Here, we discuss the insights gained so far relevant to the development of PI3K inhibitors for the treatment of human cancers. Emphasis is on the structure-activity relationship of PI3K inhibitors which bear the most significant PI3Kand#945; inhibitory activities. We also highlight PI3K inhibitors that are currently under clinical trials for cancers.

Proteasome Regulators: Activators and Inhibitors by Li Huang, Chin Chen (931-939).
This mini review covers the drug discovery aspect of both proteasome activators and inhibitors. The proteasome is involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. Due to the importance of the proteasome in cellular functions, inhibition or activation of the proteasome could become a useful therapeutic strategy for a variety of diseases. Many proteasome inhibitors have been identified and can be classified into two groups according to their source: chemically synthesized small molecules and compounds derived from natural products. A successful example of development of a proteasome inhibitor as a clinically useful drug is the peptide boronate, PS341 (Bortezomib), was approved for the treatment of multiple myeloma. In contrast to proteasome inhibitors, small molecules that can activate or enhance proteasome activity are rare and are not well studied. The fact that overexpression of the cellular proteasome activator PA28 exhibited beneficial effects on the Huntington's disease neuronal model cells raised the prospect that small molecule proteasome activators could become useful therapeutics. The beneficial effect of oleuropein, a small molecule proteasome activator, on senescence of human fibroblasts also suggested that proteasome activators might have the potential to be developed into anti-aging agents.

Soluble Forms of RAGE in Human Diseases: Clinical and Therapeutical Implications by Francesca Santilli, Natale Vazzana, Loredana Bucciarelli, Giovanni Davi (940-952).
The ligand – receptor for advanced glycation end-products (RAGE) axis has emerged as a novel pathway involved in a wide spectrum of diseases, including diabetes mellitus, atherothrombosis, chronic renal failure, rheumatoid arthritis, neurodegeneration, cancer and aging. Circulating soluble forms of RAGE (sRAGE), arising from receptor ectodomain shedding and splice variant [endogenous secretory (es) RAGE] secretion, may counteract RAGE-mediated pathogenesis, by acting as a decoy. Several studies suggest that decreased levels of sRAGE and/or esRAGE may be useful as a biomarker of ligand-RAGE pathway hyperactivity and inadequate endogenous protective response, thus providing a powerful complement to cardiovascular risk stratification and an interesting target of therapeutic interventions. This review will focus on the pathophysiological determinants of soluble forms of RAGE in different clinical settings, with particular reference to the mechanisms involved in their generation and clearance, the association with cardiovascular risk factors, the interplay with low-grade inflammation, oxidative stress and endothelial dysfunction, and the possible pharmacological modulation of their plasma levels.

Interaction modes and molecular surface properties for both peptide- and protein-antibody complexes have been investigated. Datasets were constituted from the IMGT database and consisted of 37 peptide-antibody (PEPT) and 155 protein-antibody (PROT) complexes. A computer approach was developed to analyze the surface of peptides and proteins using a level set method which allows the characterization of shape complementarity using surface curvature. We found that in both datasets, the interacting surfaces of the two binding partners, exhibited a moderate degree of shape complementarity at the molecular level but not at the atomic level. We also evaluated the structural similarity between peptides bound to antibodies and the corresponding regions in the 3D structures of the cognate proteins. We found that no more than 25and#x25; of and#966;,and#968; dihedral angles were conserved between the corresponding regions in peptides and proteins. We also superimposed the parent protein structure onto that of the bound peptides and visually looked for the presence of bumps or clashes between the cognate protein and the antibody. Except for antibodies possessing neutralizing activity and for those bound to a peptide longer than 30 residues, no superimposition in peptide-antibody complexes was found to be bump or clash-free. These findings indicate that studies restricted to continuous epitopes are unlikely to provide the information needed to design short linear peptides that could be expected to mimic satisfactorily the discontinuous epitopes of native proteins and be successful as synthetic vaccines.

The use of small molecules to specifically control important cellular functions is an area of major current interest at the interface of chemical biology and medicinal chemistry. Recognition of ribonucleic acids (RNA) has emerged more recently as a critical event in many biological pathways of eukaryotic cells and consequently the opportunity of drugs targeting to diverse structures of RNA is abundant. Such RNA targeting molecules must be able to specifically bind to unique structural organizations in RNA to regulate the gene expression. One particular example in this context is the modulation of the mRNA through its polyadenylic acid [poly(A)] tail. All mRNAs in eukaryotic cells have a poly(A) tail at the 3'-end This tail of about 200-250 or so adenine residues is an important determinant in maturation, stability of poly(A) and in initiation of translation process. Small molecules that could bind to this poly(A) tail could influence and possibly inhibit mRNA function and subsequent protein production in the cell leading to the development of new type of therapeutic agents. Recent discovery of the over expression of neo polyadenylic polymerase, the enzyme that catalyses polyadenylation, in human cancer cells compared to normal cells further signifies the importance of poly(A) in cellular events in cancer progression. The structural transition in poly(A) from single strand to double strand form induced by a narrow pH, salt and temperature variations also makes it a potential target for the better understanding of structurefunction relationship in nucleic acids. Over the last forty years attempts have been made for the structural elucidation of this polyribonucleotide as well as the complex formed by the interactions with various small molecules like DNA intercalators, partial intercalators and groove binders using various physico-chemical and technique. These studies have led to progress in the understanding of specificity of binding, correlation between structural and thermodynamic aspects, description of drug-RNA binding modes and influence of substitutents on drug-RNA complexes and ultimately the discovery of new novel compounds that can be used as modulators of poly(A) structure. This review focuses on the structural and biological significance of poly(A), the use of small molecules to control the structure of this RNA and the futuristic development of new small molecules targeted to poly(A) structures.

Atherosclerosis and hypertension are two important pathological vascular processes which share a crucial common pathway: an altered vascular homeostasis characterized by endothelial dysfunction. Carotid intima-media thickness (CIMT) measured by ultrasound has been shown to correlate with the presence of cardiovascular disease and is now widely accepted as a subclinical marker for atherosclerotic disease. Large body of evidences has shown that antihypertensive drugs exert important anti-atherosclerotic effects, which depend to some extent on the degree of blood pressure lowering provided by these drugs. Many randomized clinical trials of antihypertensive drugs (calcium channel blockers, angiotensin converting enzyme inhibitors, and#945;- and and#946;-blockers, diuretics, and angiotensin-1 receptor blockers) compared with placebo or no-treatment have demonstrated both a reduction of CIMT, a validated measure of subclinical atherosclerosis and predictor risk for clinical cardiovascular events, than a protection against clinical stroke events. However, important technical aspects of CIMT measurement must be considered. Over the last twenty years there have been great changes in the sensitivity of transducers and hence accuracy of measurement. This review explores the effectiveness of antihypertensive drugs in preventing CIMT progression and/or regression.

Type 2 Diabetes (T2D) is an important cause of renal dysfunction and the most common cause of end-stage renal disease (ESRD). Diabetic nephropathy is also associated with an increased risk of vascular disease and patient mortality. Aggressive management of hypertension to reduce microalbuminuria, together with tight glycaemic control are important therapeutic strategies for renal and vascular disease prevention in T2D. The main pathophysiological mechanisms associated with diabetic nephropathy result from activation of the renin-angiotensin-aldosterone system (RAAS), protein kinase C pathway, pro-inflammatory cytokines and various growth factors. Angiotensin II and transforming growth factor- beta (TGF-and#946;) are two important molecular mediators. The production of advanced glycation end-products (AGEs) and increased oxidative stress further exacerbates renal injury. These molecular changes within the renal tissue result in mesangial expansion, increased extracellular matrix deposition and an alteration in podocyte structure and function. Therapeutic targeting of these molecular pathways is an important area of translational research in diabetes. The elucidation of new genetic associations and proteomic biomarkers of diabetic kidney disease will also assist in the identification and treatment of high-risk patients. This review article will discuss both the molecular and clinical aspects of diabetic nephropathy, providing a bench-to-bedside research perspective to potential new therapeutic strategies.

Agonist-Trafficking and Hallucinogens by Javier Gonzalez-Maeso, Stuart Sealfon (1017-1027).
Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT2A receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

Resistance to quinolones and fluoroquinolones has been increasingly reported among human and veterinary isolates during the last three decades related to their wide clinical use. Until recently, the mechanisms of resistance to quinolones in Enterobacteriaceae were believed to be only chromosome-encoded, i.e. related to modifications of the molecular targets (DNA gyrase and topoisomerase IV), decreased outer-membrane permeability (porin defect) and overexpression of naturally-occurring efflux. However, emergence of plasmid-mediated quinolone resistance (PMQR) has been reported since 1998. Three mechanisms are known to date: Qnr proteins, aminoglycoside acetyltransferase AAC(6')-Ib-cr, and efflux pump QepA. The Qnr proteins protect DNA gyrase and type IV topoisomerase from quinolone inhibition. Four types of Qnr protiens have been reported: QnrA (six variants), QnrB (19 variants), QnrC (one variant), and QnrS (three variants). The AAC(6')-Ib-cr determinant acetylates several fluoroquinolones, such as norfloxacin and ciprofloxacin. The protein AAC(6')-Ib-cr contains two amino acid substitutions as compared to the wild-type enzyme AAC(6')-Ib. Both Qnr and AAC(6')-Ib proteins have been reported worldwide. Lately reported, the plasmid-encoded QepA efflux pump may extrude hydrophilic fluoroquinolones (eg. norfloxacin, ciprofloxacin, and enrofloxacin).