Current opinion in drug discovery & development最新文献

Research on the formation of novel enzymatic oxygenation products derived from the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has revealed the endogenous formation of several novel autacoids that have been termed resolvins and protectins. The elucidation of the chemical structures of resolvins and protectins, and the assessment of their endogenous functions, are providing a new understanding of the role of endogenous omega-3 fatty acid-derived lipid mediators in tissue protection, counteraction of inflammation and the activation of inflammation resolution. This review emphasizes the structural aspects of resolvin biosynthesis and metabolic inactivation, which are of central importance for understanding the current and future development of therapeutically relevant, stable analogs that may activate inflammation resolution.

Voltage-gated sodium (NaV1) channels in the peripheral nervous system and CNS play a critical role in pain signaling. Nociceptive neurons express several NaV1 channel subtypes that may contribute to the hyperexcitability characteristic of chronic pain states. The non-subtype selective, state-dependent NaV1 channel blockers lidocaine and carbamazepine are efficacious in the treatment of neuropathic pain; however, the target-driven development of novel sodium channel blocking analgesics has been generally unsuccessful. Recent human genetic data indicate an important role for the NaV1.7 channel subtype in pain signaling, and significant preclinical data identifies the NaV1.8 channel as a promising analgesic target, suggesting that the selective blockade of these subtypes may improve on the therapeutic index of sodium channel modulators. However, few subtype-selective small-molecule sodium channel blockers have been described. This review provides an overview of the NaV1 channel subtypes that are preferentially expressed in nociceptive neurons, the assay technologies used to develop NaV1 channel blockers, and a summary of recent advances in the development of subtype-selective and novel state-dependent NaV1 channel blockers.

The correct folding of proteins is a fundamental process in the normal physiological functioning of cells, and is mediated by cellular chaperones including members of the Hsp70 family. Many diseases are caused by a failure of cellular chaperones to adequately maintain correct protein folding, and has led to the development of a therapeutic strategy to upregulate the activity of cellular chaperones in order to ameliorate intrinsic folding deficits. A large range of pharmacological agents that can induce cellular chaperones and correct deficits associated with misfolded proteins are known. This review surveys the mechanisms and compounds that have been used to modulate cellular chaperones, and discusses the continuing challenges in translating this approach into clinical improvements in the treatment of protein misfolding disorders.

The pharmaceutical industry has traditionally targeted the inhibition of dysregulated kinases to treat diseases such as cancer and inflammatory disorders. In contrast to the human genome sequencing project, which aimed to identify novel biological targets, the possibility of activating kinases uses known targets in a novel manner. In an approach that is similar to other target classes (eg, GPCRs and nuclear receptors), transient upregulation of kinase function using small molecules has been increasingly demonstrated to lead to favorable disease outcomes. This review discusses direct small-molecule kinase activators: specifically, how these molecules were discovered, characterized, evaluated and developed into drug leads. The choice of potential targets, the mechanisms of activation and the common strategies used to discover activators are also highlighted.

Once regarded as an irreversible modification, the methylation of histone protein tails has recently been highlighted following the identification of enzymes capable of histone demethylation in response to developmental or environmental cues. An awareness of the dynamic nature of histone modification has stimulated interest in the concept that drugs targeting histone methylation/demethylation might provide treatments for cancer, inflammation and metabolic disorders. However, epigenetic therapies that target histone demethylation are at the concept stage. Histone demethylases and their potential as therapeutic targets are discussed in this review.

The acetylation of histone lysine is central to providing the dynamic regulation of chromatin-based gene transcription. The bromodomain (BRD), which is the conserved structural module in chromatin-associated proteins and histone acetyltranferases, is the sole protein domain known to recognize acetyl-lysine residues on proteins. Structural analyses of the recognition of lysine-acetylated peptides derived from histones and cellular proteins by BRDs have provided new insights into the differences between and unifying features of the selectivity that BRDs exhibit in binding biological ligands. Recent research has highlighted the importance of BRD/acetyl-lysine binding in orchestrating molecular interactions in chromatin biology and regulating gene transcription. These studies suggest that modulating BRD/acetyl-lysine interactions with small molecules may provide new opportunities for the control of gene expression in human health and disease.

Low pH in tissue can evoke pain in animals and humans, and is an important factor in hyperalgesia. Research has also implicated acidosis in psychiatric and neurological diseases. One emerging class of pH-detecting receptors is that of the acid-sensing ion channels (ASICs). Advances in ASIC research have improved the understanding of the role played by pH dynamics in physiological and pathophysiological processes. Increasing evidence suggests that targeting ASICs with pharmacological agents may offer an effective and novel approach for treating pain and diseases of the CNS. However, the development of pharmaceuticals that target ASICs and are suitable for clinical use remains an obstacle. This review provides an update on ASICs and their potential for therapeutic modification in pain and CNS diseases.

The importance of kinetics in drug-target interactions, and particularly the residence time of a drug with its target, is increasingly recognized to play a pivotal role in determining both the efficacy and toxicity of a drug. Drug residence time can often be demonstrated to be a key differentiating factor between drugs that act upon a common target. Drug-target residence time can result in either favorable or unfavorable outcomes, and the use of such information could lead to the more efficient design of best-in-class drugs. This review highlights several key concepts and observations related to drug-target residence time, and suggests the use of a kinetics-perceptive and energetics-informed approach to address the challenges facing current drug discovery efforts.

PDE10A is a dual substrate PDE that is highly expressed in medium spiny neurons of the striatal complex. The inhibition of PDE10A produces effects that modulate basal ganglia function in ways that suggest a particular therapeutic utility in the treatment of psychosis in schizophrenia. Significant understanding of PDE10A at the molecular level has helped to guide efforts in inhibitor design, and many different inhibitor classes have now been discovered. At least one PDE10A inhibitor has been advanced into clinical trials to begin to test the hypothesis that such agents may be useful in the treatment of psychosis.

The development of Aurora kinase inhibitors is a competitive research field, with many inhibitors currently being evaluated in preclinical and clinical studies. Progress during the past few years, both preclinically and clinically, has increased the evidence supporting Aurora kinases as promising molecular targets for the treatment of cancer. Aurora kinase inhibitors differ based on their selectivity within the Aurora kinase family and their cross-reactivities with other kinases. Additional factors that will contribute to the success or failure of the Aurora kinase inhibitors include: routes of administration, drug-like properties, workable combinations with approved drugs, adequate clinical development paths, and the identification of the appropriate patient population. The clinical trial results that are emerging for the most advanced inhibitors are promising, and it is probable that clinical proof of concept will be achieved, and that Aurora kinase inhibitors will be part of treatment for cancer in the future.