The Keap1–Nrf2–ARE ((Kelch‐like ECH‐Associating protein 1) nuclear factor erythroid 2 related factor 2‐antioxidant response element) pathway is one of the most important defense mechanisms against oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1–Nrf2–ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first‐line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO‐Me, was terminated for safety reasons. Directly inhibiting Keap1–Nrf2 protein–protein interactions as a novel Nrf2‐modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1–Nrf2 protein–protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. In addition, inhibiting Nrf2 activity has attracted an increasing amount of attention because it may provide an alternative cancer therapy. This review summarizes the molecular mechanisms and biological functions of the Keap1–Nrf2–ARE system. The main focus of this review is on recent progress in studies of agents that target the Keap1–Nrf2–ARE pathway and the therapeutic applications of such agents.
Fibroblast growth factors (FGFs) are involved in a variety of cellular processes, such as stemness, proliferation, anti‐apoptosis, drug resistance, and angiogenesis. Here, FGF signaling network, cancer genetics/genomics of FGF receptors (FGFRs), and FGFR‐targeted therapeutics will be reviewed. FGF signaling to RAS‐MAPK branch and canonical WNT signaling cascade mutually regulate transcription programming. FGF signaling to PI3K‐AKT branch and Hedgehog, Notch, TGFβ, and noncanonical WNT signaling cascades regulate epithelial‐to‐mesenchymal transition (EMT) and invasion. Gene amplification of FGFR1 occurs in lung cancer and estrogen receptor (ER)‐positive breast cancer, and that of FGFR2 in diffuse‐type gastric cancer and triple‐negative breast cancer. Chromosomal translocation of FGFR1 occurs in the 8p11 myeloproliferative syndrome and alveolar rhabdomyosarcoma, as with FGFR3 in multiple myeloma and peripheral T‐cell lymphoma. FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively, due to interstitial deletions in glioblastoma multiforme. Missense mutations of FGFR2 are found in endometrial uterine cancer and melanoma, and similar FGFR3 mutations in invasive bladder tumors, and FGFR4 mutations in rhabdomyosarcoma. Dovitinib, Ki23057, ponatinib, and AZD4547 are orally bioavailable FGFR inhibitors, which have demonstrated striking effects in preclinical model experiments. Dovitinib, ponatinib, and AZD4547 are currently in clinical trial as anticancer drugs. Because there are multiple mechanisms of actions for FGFR inhibitors to overcome drug resistance, FGFR‐targeted therapy is a promising strategy for the treatment of refractory cancer. Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR‐targeted therapeutics in the era of personalized medicine.
Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta‐amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current “anti‐Alzheimer's” agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov , and on database of the website Alzforum.org . As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so‐called “disease‐modifying agents”) — these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti‐Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials.
The emergence of multidrug‐resistant bacteria has placed a strain on health care systems and highlighted the need for new classes of antibiotics. Bacterial lipopeptides are secondary metabolites, generally produced by nonribosomal peptide synthetases that often exhibit broad‐spectrum antimicrobial activity. Only two new structural types of antibiotics have entered the market in the last 40 years, linezolid and the bacterial lipopeptide daptomycin. A wide variety of bacteria produce lipopeptides, however Bacillus and Paenibacillus spp. in particular have yielded several potent antimicrobial lipopeptides. Many of the lipopeptides produced by these bacteria have been known for decades and represent a potential gold mine of antibiotic candidates. This list includes the polymyxins, octapeptins, polypeptins, iturins, surfactins, fengycins, fusaricidins, and tridecaptins, as well as some novel examples, including the kurstakins. These lipopeptides have a wide variety of activities, ranging from antibacterial and antifungal, to anticancer and antiviral. This review presents a reasonably comprehensive list of each class of lipopeptide and their known homologues. Emphasis has been placed on their antimicrobial activities, as well other potential applications for this interesting class of substances.
Gold compounds are a class of metallodrugs with great potential for cancer treatment. During the last two decades, a large variety of gold(I) and gold(III) compounds are reported to possess relevant antiproliferative properties in vitro against selected human tumor cell lines, qualifying themselves as excellent candidates for further pharmacological evaluation. The unique chemical properties of the gold center confer very interesting and innovative pharmacological profiles to gold-based metallodrugs. The primary goal of this review is to define the state of the art of preclinical studies on anticancer gold compounds, carried out either in vitro or in vivo. The available investigations of anticancer gold compounds are analyzed in detail, and particular attention is devoted to underlying molecular mechanisms. Notably, a few biophysical studies reveal that the interactions of cytotoxic gold compounds with DNA are generally far weaker than those of platinum drugs, implying the occurrence of a substantially different mode of action. A variety of alternative mechanisms were thus proposed, of which those involving either direct mitochondrial damage or proteasome inhibition or modulation of specific kinases are now highly credited. The overall perspectives on the development of gold compounds as effective anticancer drugs with an innovative mechanism of action are critically discussed on the basis of the available experimental evidence. .
Plumbagin is one of the simplest plant secondary metabolite of three major phylogenic families viz. Plumbaginaceae , Droseraceae , and Ebenceae , and exhibits highly potent biological activities, including antioxidant, antiinflammatory, anticancer, antibacterial, and antifungal activities. Recent investigations indicate that these activities arise mainly out of its ability to undergo redox cycling, generating reactive oxygen species and chelating trace metals in biological system. The compound is endowed with a property to inhibit the drug efflux mechanism in drug‐resistant bacteria, thereby allowing intracellular accumulation of the potent drug molecules. An interesting bioactivity exhibited by this compound is the elimination of stringent, conjugative, multidrug‐resistant plasmids from several bacterial strains including opportunistic bacteria, such as Acinetobacter baumannii . Moreover, plumbagin effectively induces apoptosis and causes cell cycle arrest, which is, in part, due to the inactivation of NF‐κB in cancer cells. Therefore, it has been suggested that designing “hybrid drug molecules” of plumbagin by combining it with other appropriate anticancer agents may lead to the generation of novel and potent anticancer drugs with pleiotropic action against human cancers. This comprehensive review is an attempt to understand the chemistry of plumbagin and catalog its biological activities reported to date.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent very potent and most promising anti‐AIDS agents that specifically target the HIV‐1 reverse transcriptase (RT). However, the effectiveness of NNRTI drugs can be hampered by rapid emergence of drug‐resistant viruses and severe side effects upon long‐term use. Therefore, there is an urgent need to develop novel, highly potent NNRTIs with broad spectrum antiviral activity and improved pharmacokinetic properties, and more efficient strategies that facilitate and shorten the drug discovery process would be extremely beneficial. Fortunately, the structural diversity of NNRTIs provided a wide space for novel lead discovery, and the pharmacophore similarity of NNRTIs gave valuable hints for lead discovery and optimization. More importantly, with the continued efforts in the development of computational tools and increased crystallographic information on RT/NNRTI complexes, structure‐based approaches using a combination of traditional medicinal chemistry, structural biology, and computational chemistry are being used increasingly in the design of NNRTIs. First, this review covers two decades of research and development for various NNRTI families based on their chemical scaffolds, and then describes the structural similarity of NNRTIs. We have attempted to assemble a comprehensive overview of the general approaches in NNRTI lead discovery and optimization reported in the literature during the last decade. The successful applications of medicinal chemistry strategies, crystallography, and computational tools for designing novel NNRTIs are highlighted. Future directions for research are also outlined.
Salvia miltiorrhiza Bunge (Danshen in Chinese) is a classical Huoxue Huayu (a traditional Chinese medical term means promoting blood circulation and removing blood stasis) herb with 1000 years of clinical application. It mainly contains two groups of ingredients: the hydrophilic phenolic acids and the lipophilic tanshinones. Both groups have demonstrated multiple bioactivities, such as antioxidative stress, antiplatelet aggregation, anti‐inflammation, among others. Recent data have demonstrated that its lipophilic compounds, especially the tanshinones, show potent anticancer activities both in vitro and in vivo. The anticancer effects of the hydrophilic phenolic acids have also been reported. Furthermore, tanshinones provide structural skeletons for chemical modifications, allowing for a series of derivatives of interests. This review provides a systematic summary of the anticancer profile and the underlying mechanisms of the bioactive compounds isolated from Danshen with special emphasis on tanshinones, aiming to bring new insights for further research and development of this ancient herb.
In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.
A vast number of marketed drugs act on G protein‐coupled receptors (GPCRs), the most successful category of drug targets to date. These drugs usually possess high target affinity and selectivity, and such combined features have been the driving force in the early phases of drug discovery. However, attrition has also been high. Many investigational new drugs eventually fail in clinical trials due to a demonstrated lack of efficacy. A retrospective assessment of successfully launched drugs revealed that their beneficial effects in patients may be attributed to their long drug‐target residence times (RTs). Likewise, for some other GPCR drugs short RT could be beneficial to reduce the potential for on‐target side effects. Hence, the compounds’ kinetics behavior might in fact be the guiding principle to obtain a desired and durable effect in vivo . We therefore propose that drug‐target RT should be taken into account as an additional parameter in the lead selection and optimization process. This should ultimately lead to an increased number of candidate drugs moving to the preclinical development phase and on to the market. This review contains examples of the kinetics behavior of GPCR ligands with improved in vivo efficacy and summarizes methods for assessing drug‐target RT.
Many studies have been carried out for early diagnosis of complex diseases by finding accurate and robust biomarkers specific to respective diseases. In particular, recent rapid advance of high‐throughput technologies provides unprecedented rich information to characterize various disease genotypes and phenotypes in a global and also dynamical manner, which significantly accelerates the study of biomarkers from both theoretical and clinical perspectives. Traditionally, molecular biomarkers that distinguish disease samples from normal samples are widely adopted in clinical practices due to their ease of data measurement. However, many of them suffer from low coverage and high false‐positive rates or high false‐negative rates, which seriously limit their further clinical applications. To overcome those difficulties, network biomarkers (or module biomarkers) attract much attention and also achieve better performance because a network (or subnetwork) is considered to be a more robust form to characterize diseases than individual molecules. But, both molecular biomarkers and network biomarkers mainly distinguish disease samples from normal samples, and they generally cannot ensure to identify predisease samples due to their static nature, thereby lacking ability to early diagnosis. Based on nonlinear dynamical theory and complex network theory, a new concept of dynamical network biomarkers (DNBs, or a dynamical network of biomarkers) has been developed, which is different from traditional static approaches, and the DNB is able to distinguish a predisease state from normal and disease states by even a small number of samples, and therefore has great potential to achieve “real” early diagnosis of complex diseases. In this paper, we comprehensively review the recent advances and developments on molecular biomarkers, network biomarkers, and DNBs in particular, focusing on the biomarkers for early diagnosis of complex diseases considering a small number of samples and high‐throughput data (or big data). Detailed comparisons of various types of biomarkers as well as their applications are also discussed.
Histone lysine‐specific demethylase 1 (LSD1) is the first discovered and reported histone demethylase by Dr. Shi Yang's group in 2004. It is classified as a member of amine oxidase superfamily, the common feature of which is using the flavin adenine dinucleotide (FAD) as its cofactor. Since it is located in cell nucleus and acts as a histone methylation eraser, LSD1 specifically removes mono‐ or dimethylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through formaldehyde‐generating oxidation. It has been indicated that LSD1 and its downstream targets are involved in a wide range of biological courses, including embryonic development and tumor‐cell growth and metastasis. LSD1 has been reported to be overexpressed in variety of tumors. Inactivating LSD1 or downregulating its expression inhibits cancer‐cell development. LSD1 targeting inhibitors may represent a new insight in anticancer drug discovery. This review summarizes recent studies about LSD1 and mainly focuses on the basic physiological function of LSD1 and its involved mechanisms in pathophysiologic conditions, as well as the development of LSD1 inhibitors as potential anticancer therapeutic agents.
Carbohydrates are known to mediate a large number of biological and pathological events. Small and macromolecules capable of carbohydrate recognition have great potentials as research tools, diagnostics, vectors for targeted delivery of therapeutic and imaging agents, and therapeutic agents. However, this potential is far from being realized. One key issue is the difficulty in the development of "binders" capable of specific recognition of carbohydrates of biological relevance. This review discusses systematically the general approaches that are available in developing carbohydrate sensors and "binders/receptors," and their applications. The focus is oil discoveries during the last 5 Wars. (C) 2009 Wiley Periodicals, Inc. Med Res Rev, 30. No. 2. 171-257, 2010
The proviral insertion site in Moloney murine leukemia virus, or PIM proteins, are a family of serine/threonine kinases composed of three different isoforms ( PIM1 , PIM2 , and PIM3 ) that are highly evolutionarily conserved. These proteins are regulated primarily by transcription and stability through pathways that are controlled by Janus kinase/Signal transducer and activator of transcription, JAK/STAT, transcription factors. The PIM family proteins have been found to be overexpressed in hematological malignancies and solid tumors, and their roles in these tumors were confirmed in mouse tumor models. Furthermore, the PIM family proteins have been implicated in the regulation of apoptosis, metabolism, cell cycle, and homing and migration, which has led to the postulation of these proteins as interesting targets for anticancer drug discovery. In the present work, we review the importance of PIM kinases in tumor growth and as drug targets.