Novel strategies for inhibition of the p38 MAPK pathway

The p38 subgroup of the mitogen-activated protein kinase superfamily has four isoforms: p38alpha, p38beta, p38delta and p38gamma. Whereas p38alpha is involved in inflammation, proliferation, differentiation and apoptosis, the biological functions of p38beta, p38delta and p38gamma are not understood completely. Many p38alpha inhibitors with diverse chemical structures and modes of protein interaction have been designed on the basis of their ability to compete with ATP for binding to p38alpha. Although some of these inhibitors show anti-inflammatory effects in animal models, they have repeatedly failed in clinical trials, highlighting the need for better approaches to inhibitor design. Here, we discuss alternative strategies that might lead to better p38 inhibitors, including non-ATP-competitive inhibitors and inhibitors that are targeted to other components of the signaling pathway.     

Deciphering calcineurin inhibitor nephrotoxicity: a pharmacological approach

The calcineurin inhibitors ciclosporin and tacrolimus are used to prevent acute rejection of solid organs after transplantation. Their use can lead to chronic renal damage characterized by progressive and irreversible deterioration of renal function associated with interstitial fibrosis, tubular atrophy, arteriolar hyalinosis and glomerulosclerosis. Many approaches to better understand the mechanisms of this toxicity are in use. The aim of these approaches is to find biomarkers of early kidney injury and potential therapeutic targets. Despite these efforts, the biological processes leading to calcineurin inhibitor nephrotoxicity remain poorly understood. Furthermore, the diagnosis of chronic renal damage remains inaccurate without definitive diagnostic tools, no effective prevention exists and a therapy to treat the damage has yet to be developed. In this article, theories of pharmacodynamics, pharmacokinetics, therapeutic drug monitoring and pharmacogenetics are synthesized in ways that may improve the understanding of mechanisms leading to calcineurin inhibitor toxicity. The importance of global approaches such as toxicogenomics is emphasized to characterize early cellular responses implicated in calcineurin inhibitor nephrotoxicity.     

Pharmacological treatments for prostate cancer

Recently, chemotherapy for prostate cancer has been primarily reserved for the palliation of symptoms secondary to prostate cancer. Chemotherapy regimens and new approaches are being developed that offer new hope of response and improved survival to men with prostate cancer. This paper discusses pharmacological strategies that are under investigation: cytotoxic agents and biological or targeted therapies, including the microtubule inhibitors (taxane/taxoids, vinorelbine) alone and in novel combinations with other experimental agents such calcitriol, thalidomide or flavopiridol (cell-cycle inhibitor) and treatment with epothilone analogues; endothelin receptor antagonists; other novel strategies such as vaccine therapy (GVAX; Cell Genesys) and prostate-specific membrane antibodies; and bisphosphonates.     

Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer

The p21-activated kinases (PAKs), immediate downstream effectors of the small G-proteins of the Rac/cdc42 family, are critical mediators of signaling pathways regulating cellular behaviors and as such, have been implicated in pathological conditions including cancer. Recent studies have validated the requirement for PAKs in promoting tumorigenesis in breast carcinoma and neurofibromatosis. Thus, there has been considerable interest in the development of inhibitors to the PAKs, as biological markers and leads for the development of therapeutics. While initial approaches were based on screening for competitive organic inhibitors, more recent efforts have focused on the identification of allosteric inhibitors, organometallic ATP-competitive inhibitors and the use of PAK1/inhibitor crystal structures for inhibitor optimization. This has led to the identification of highly selective and potent inhibitors, which will serve as a basis for further development of inhibitors for therapeutic applications.     

Pharmacological treatments for prostate cancer

Recently, chemotherapy for prostate cancer has been primarily reserved for the palliation of symptoms secondary to prostate cancer. Chemotherapy regimens and new approaches are being developed that offer new hope of response and improved survival to men with prostate cancer. This paper discusses pharmacological strategies that are under investigation: cytotoxic agents and biological or targeted therapies, including the microtubule inhibitors (taxane/taxoids, vinorelbine) alone and in novel combinations with other experimental agents such calcitriol, thalidomide or flavopiridol (cell-cycle inhibitor) and treatment with epothilone analogues; endothelin receptor antagonists; other novel strategies such as vaccine therapy (GVAX^®; Cell Genesys) and prostate-specific membrane antibodies; and bisphosphonates.     

Strategies for the identification of inhibitors of West Nile virus and other flaviviruses

The recent outbreaks of West Nile virus (WNV) and other emerging and re-emerging flaviviruses, have made prevention and treatment of flavivirus infections a global public health priority. No inhibitor is currently available for use as an antiflavivirus therapy. In this communication, I review (i) stages of flavivirus replication representing potential targets for antiviral drug discovery; (ii) strategies for identification of flavivirus inhibitors; and (iii) existing antiviral inhibitors reported to have anti-WNV or other antiflavivirus activities. Flaviviruses share conserved nucleotide elements and amino acid sequences, and have similar genome organization and replication strategies. As such, it is hoped that broad spectrum flavivirus inhibitors could be identified through screening of compound libraries.     

The emerging role of poly(ADP-Ribose) polymerase inhibitors in cancer treatment

Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors have been shown to sensitize tumors to DNA-damaging agents and to also selectively kill homologous recombination repair-defective cancers, such as those arising in BRCA1 and BRCA2 mutation carriers. Recent proof-of-concept clinical studies have demonstrated the safety and substantial antitumor activity of the PARP inhibitor, olaparib in BRCA1/2 mutation carriers, highlighting the wide therapeutic window that can be achieved with this synthetic lethal strategy. Likewise, the PARP inhibitor, BSI-201, in combination with carboplatin and gemcitabine have produced promising results in "triple-negative" breast cancers. There are also currently numerous other PARP inhibitors in clinical development. The potential broader therapeutic application of these approaches to a wide range of sporadic tumors harboring specific defects in the homologous recombination repair pathway has generated a great deal of excitement within the oncology community. This review discusses the rationale for targeting PARP and details the strategies and challenges involved in the clinical development of such inhibitors and their future potential applications in cancer medicine.     

口服降糖药二肽基肽酶Ⅳ（DPP-4）抑制剂的多器官保护作用

二肽基肽酶Ⅳ（DPP-4）抑制剂是近年来新上市的一种新型口服降糖药物。 DPP-4抑制剂通过抑制DPP-4来抑制胰岛素多肽（GIP）和胰高血糖素样肽1（GLP-1）降解,发挥降低血糖的作用。 DPP-4抑制剂不仅能双向控制血糖,且具有降糖外的胰腺、心血管、肾脏、肝脏等多器官保护作用和抗炎作用。本文对已有的DPP-4抑制剂及其多器官保护作用进行综述,总结其优势及进一步发展的趋势,为临床用药提供参考。     

Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.     

An update on the discovery and development of selective heat shock protein inhibitors as anti-cancer therapy

ABSTRACT

Introduction: Over the years, not a single HSP inhibitor has progressed into the post-market phase of drug development despite the success recorded in various pre-clinical and clinical studies. The inability of existing drugs to specifically target oncogenic HSPs has majorly accounted for these setbacks. Recent combinatorial strategies that incorporated computer-aided drug design (CADD) techniques are geared towards the development of highly specific HSP inhibitors with increased activities and minimal toxicities.

Areas covered: In this review, strategic therapeutic approaches that have recently aided the development of selective HSP inhibitors were highlighted. Also, the significant contributions of CADD techniques over the years were discussed in detail. This article further describes promising computational paradigms and their applications towards the discovery of highly specific inhibitors of oncogenic HSPs.

Expert opinion: The recent shift towards highly selective and specific HSP inhibition has shown great promise as evidenced by the development of paralog/isoform-selective HSP drugs. It could be further augmented with computer-aided drug design strategies, which incorporate reliable methods that would greatly enhance the design and optimization of novel inhibitors with improved activities and minimal toxicities.     

PDE4 inhibitors: a review of current developments (2005 – 2009)

Background: Despite the sound preclinical database and some promising data from clinical trials, development of PDE4 inhibitors for the treatment of inflammatory or neurological diseases has been hampered by dose-limiting class-related side effects. Objective: In the past years, companies opted for different approaches to improve the therapeutic window of their compounds including topical administration of PDE4 inhibitors with the goal of minimizing systemic exposure. This change in strategy is reflected by the disclosure of novel and chemically diverse molecules that demonstrate the continued interest of pharmaceutical industry in developing PDE4 inhibitors. Conclusion: This review summarizes the clinical development of PDE4 inhibitors since 2005 and the associated patent literature with a focus on strategies applied to minimize systemic adverse effects. In sum, although a significant number of new drugs designed for improved tolerability entered clinical trials, so far none of them fulfilled expectations and best progress has been achieved recently with the oral, non-isoform selective PDE4 inhibitor roflumilast.     

Guidelines for the appropriate use of non-steroidal anti-inflammatory drugs, cyclo-oxygenase-2-specific inhibitors and proton pump inhibitors in patients requiring chronic anti-inflammatory therapy

AIM: To rationalize decision making around the use of different non-steroidal anti-inflammatory drug (NSAID) treatment strategies in patients with varying degrees of gastrointestinal and cardiovascular risk. METHODS: The panel comprised nine physicians (three rheumatologists, two internists, two gastroenterologists and two cardiologists) from geographically diverse areas practising in community-based settings (n = 4) and academic institutions (n = 5). A literature review was performed by the authors on the risks, benefits and costs of NSAIDs, cyclo-oxygenase-2-specific inhibitors and proton pump inhibitor co-therapy. The RAND/UCLA Appropriateness Method was used to rate 304 clinical scenarios as 'appropriate', 'uncertain' or 'inappropriate'. RESULTS: In patients with no previous gastrointestinal event and not concurrently on aspirin (low risk), the panel rated the use of an NSAID alone as 'appropriate' for those aged < 65 years, and the use of an NSAID +proton pump inhibitor or cyclo-oxygenase-2-specific inhibitor + proton pump inhibitor as 'inappropriate'. For patients aged > 65 years and at low risk, an NSAID or cyclo-oxygenase-2-specific inhibitor alone was rated as 'uncertain'. For patients with a previous gastrointestinal event or who concurrently received aspirin, an NSAID alone was rated as 'inappropriate', and either a cyclo-oxygenase-2-specific inhibitor or an NSAID +proton pump inhibitor was rated as 'appropriate'. Finally, for patients with a previous gastrointestinal event and on aspirin, an NSAID or cyclo-oxygenase-2-specific inhibitor in conjunction with a proton pump inhibitor was rated as 'appropriate'. CONCLUSIONS: Clinicians and managed care entities need to balance the risks, benefits and costs of NSAIDs, cyclo-oxygenase-2-specific inhibitors and the prophylactic use of proton pump inhibitors. The guidelines given here can assist this process.     

Targeting EGFR in pancreatic cancer treatment

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90% of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.     

抗阿尔茨海默病的胆碱酯酶抑制剂研究进展

目前抗阿尔茨海默病的新策略之一是设计具有多靶向的药物。综述抗阿尔茨海默病的胆碱酯酶抑制剂研究的新进展,分类介绍乙酰胆碱酯酶和丁酰胆碱酯酶双重抑制剂、可抑制B-淀粉样蛋白聚集的胆碱酯酶抑制剂、具有抗氧化作用的胆碱酯酶抑制剂、可拮抗H,受体的胆碱酯酶抑制剂以及NO供体型胆碱酯酶抑制剂等多靶向药物,并讨论了各类药物的设计和优化。     

beta-Lactamase epidemiology and the utility of established and novel beta-lactamase inhibitors

beta-Lactamase inhibitor:beta-lactam combinations remain one of the most successful strategies for the treatment of bacterial infections. Over the last 20 years the number and diversity of serine and metallo active site beta-lactamases has increased dramatically. This review highlights some of the new additions to the beta-lactamase arena and discusses how the commercially available beta-lactamase inhibitors are keeping pace with the changing epidemiology of beta-lactamases. In addition, we survey the progress with the design of novel inhibitors of serine and metallo-beta-lactamases. Focus is given to the recent advances in the design of metallo-beta-lactamase inhibitors as these enzymes pose a serious emerging threat to the use of all beta-lactam based therapies.     

Conformational selection of inhibitors and substrates by proteolytic enzymes: implications for drug design and polypeptide processing

Inhibitors of proteolytic enzymes (proteases) are emerging as prospective treatments for diseases such as AIDS and viral infections, cancers, inflammatory disorders, and Alzheimer's disease. Generic approaches to the design of protease inhibitors are limited by the unpredictability of interactions between, and structural changes to, inhibitor and protease during binding. A computer analysis of superimposed crystal structures for 266 small molecule inhibitors bound to 48 proteases (16 aspartic, 17 serine, 8 cysteine, and 7 metallo) provides the first conclusive proof that inhibitors, including substrate analogues, commonly bind in an extended beta-strand conformation at the active sites of all these proteases. Representative superimposed structures are shown for (a) multiple inhibitors bound to a protease of each class, (b) single inhibitors each bound to multiple proteases, and (c) conformationally constrained inhibitors bound to proteases. Thus inhibitor/substrate conformation, rather than sequence/composition alone, influences protease recognition, and this has profound implications for inhibitor design. This conclusion is supported by NMR, CD, and binding studies for HIV-1 protease inhibitors/substrates which, when preorganized in an extended conformation, have significantly higher protease affinity. Recognition is dependent upon conformational equilibria since helical and turn peptide conformations are not processed by proteases. Conformational selection explains the resistance of folded/structured regions of proteins to proteolytic degradation, the susceptibility of denatured proteins to processing, and the higher affinity of conformationally constrained 'extended' inhibitors/substrates for proteases. Other approaches to extended inhibitor conformations should similarly lead to high-affinity binding to a protease.     

Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complications--review and recommendations based on risk assessment

The incidence of non-steroidal anti-inflammatory drug-related ulcer complications remains high despite the availability of potent anti-ulcer drugs and selective cyclo-oxygenase-2 inhibitors. Non-steroidal anti-inflammatory drug-related ulcer complications can be minimized by prospective assessment of patients' baseline risk, rational choice and use of non-steroidal anti-inflammatory drugs, and selective use of co-therapy strategies with gastroprotectives. Current recommendations regarding strategies using anti-ulcer drugs and cyclo-oxygenase-2 inhibitors for prevention of clinical non-steroidal anti-inflammatory drug upper gastrointestinal events are largely derived from studies using surrogates such as endoscopic ulcers, erosions, and symptoms in low- to average-risk patients. Conclusions based on surrogate and potentially manipulatable end-points are increasingly suspect with regard to applicability to clinical situations. This article reviews the risks associated with non-steroidal anti-inflammatory drugs including aspirin and includes the effect of the patients' baseline risk, and the confounding effects of Helicobacter pylori infection. In addition, uncertainties regarding the clinical efficacy of anti-ulcer drugs and cyclo-oxygenase-2 inhibitors against non-steroidal anti-inflammatory drug-related ulcer complications are put into perspective. We propose management strategies based on the risk category: low risk (absence of risk factors) (least ulcerogenic non-steroidal anti-inflammatory drug at lowest effective dose), moderate risk (one to two risk factors) (as above, plus an antisecretory agent or misoprostol or a cyclo-oxygenase-2 inhibitor), high risk (multiple risk factors or patients using concomitant low-dose aspirin, steroids, or anticoagulants) (cyclo-oxygenase-2 inhibitor alone with steroids, plus misoprostol with warfarin, or plus a proton pump inhibitors or misoprostol with aspirin), and very high risk (history of ulcer complications) (avoid all non-steroidal anti-inflammatory drugs, if possible or a cyclo-oxygenase-2 plus a proton pump inhibitors and/or misoprostol). The presence of H. pylori infection increases the risk of upper gastrointestinal complications in non-steroidal anti-inflammatory drug users by two- to fourfold suggesting that all patients requiring regular non-steroidal anti-inflammatory drug therapy be tested for H. pylori.     

Tyrosine Kinase Inhibitors in Preclinical Development

Due to the limited efficacy of cytotoxic chemotherapy in the treatment of advanced malignancy and its excessive toxicity precluding its use in chemoprevention, new therapeutic and preventive strategies have been sought. One of the most interesting of these new approaches is the manipulation of signal transduction pathways. Among the approaches being considered to eventuate such a strategy is the inhibition of autophosphorylation, a critical first step in the signal transduction pathways of many cell surface receptor tyrosine kinases, as well as of non-receptor tyrosine kinases. This article is intended to review those tyrosine kinase inhibitors that are currently in preclinical development, for which there are data to support consideration for their use in chemoprevention or cancer treatment. We will focus upon those agents that have received attention in the past several years.