New small-molecule inhibitors of mitogen-activated protein kinase kinase

Background: Overexpression of the Ras/Raf/MEK/ERK (extracellular-signal-regulated kinase) pathway is associated with the formation, progression and survival of tumours and has also been implicated in a diverse range of therapeutic areas such as arthritis, organ transplant rejection, asthma and developmental disorders. One approach to down regulation of this pathway is through the inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2). Objective: The importance of the mitogen-activated protein kinase (MAPK) pathway, MEK1/2 as a therapeutic target and early MEK1/2 inhibitors is discussed, followed by an overview of recent patent activity in the area. Methods: The patent literature was searched for inhibitors of MEK1/2 published within the last three years; these results are described. Other relevant publications that provide further insight into the discovery and development of these compounds are also discussed. Conclusion: The determination of a crystal structure with inhibitor bound has allowed the design of exquisitely selective and potent inhibitors of MEK1/2. Several allosteric inhibitors have advanced to clinical trial and shown some efficacy in cancer as single agents, but the future application of MEK1/2 inhibitors is likely to be either in combination with other therapies or in disorders which are genetically defined as being dependent on the MAPK pathway.     

Apoptosis: potential therapeutic targets for new drug discovery

Apoptosis is involved in a wide range of pathologic conditions, including neurodegenerative, autoimmune diseases, cardiovascular diseases and cancer. Therefore, the ability to understand and manipulate the cell death machinery is an obvious goal of medical research. Novel therapeutic approaches to modulate disease by regulating apoptosis are being tested in preclinical and clinical settings. Approaches include the traditional use of small molecules to target specific players in the apoptosis cascade. As our understanding of apoptosis increases, further opportunities will arise for tailor-made therapies that will result in improved clinic. From variety of compounds are discovered in this field and only few are found in the preclinical and clinical trials. The lack of specific potent nonpeptide apoptosis inducers and/or inhibitors has limited for a long time the clinical investigation of this target. But in the last few years the renewed interest of pharmaceutical companies has been giving a strong impulse to the research in this area. This review considers the molecular mechanisms of apoptosis and their interaction in regulation of apoptosis. We also focus on recent developments of nonpeptide apoptosis modulators and their progress in drug lead discovery.     

TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery

Dysregulation of TANK-binding kinase 1 (TBK1) homeostasis leads to the occurrence and progression of many diseases, such as inflammation, autoimmune diseases, metabolic diseases, and cancer. Therefore, there is a need to develop TBK1 inhibitors as therapeutic agents. In this review, we highlight the diverse biological functions of TBK1 and summarize the promising small-molecule inhibitors of TBK1 that have the potential to be developed as therapeutic candidates.     

Antibody-enabled small-molecule drug discovery

Although antibody-based therapeutics have become firmly established as medicines for serious diseases, the value of antibodies as tools in the early stages of small-molecule drug discovery is only beginning to be realized. In particular, antibodies may provide information to reduce risk in small-molecule drug discovery by enabling the validation of targets and by providing insights into the design of small-molecule screening assays. Moreover, antibodies can act as guides in the quest for small molecules that have the ability to modulate protein-protein interactions, which have traditionally only been considered to be tractable targets for biological drugs. The development of small molecules that have similar therapeutic effects to current biologics has the potential to benefit a broader range of patients at earlier stages of disease.     

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.     

Novel mitotic targets and their small-molecule inhibitors

With several successful anticancer drugs on the market and numerous compounds in clinical developments, antimitotic agents represent an important category of anticancer agents. However, clinical utility of the tubulin-binding agents is somewhat limited due to multiple drug resistance (MDR), poor pharmacokinetics and therapeutic index. There is ongoing need for the modulators of other intracellular targets that result in the same anti-mitotic effect without adverse effects of "traditional" tubulin binders. This review describes progress made to-date in development of novel and emerging biotargets affecting the mitotic events, and their small-molecule modulators.     

Glycobiology of the Leishmania parasite and emerging targets for antileishmanial drug discovery

Importance of the field: Parasitic diseases that pose a threat to human life include leishmaniasis – caused by protozoa of Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity and factors like cost and drug resistance, thus furthering the need to develop this area of research.

Areas covered in this review: We came across drug targets, very recently characterised, cloned and validated by genomics and bioinformatics. We bring these promising drug targets into focus so that they can be explored to their fullest.

What the reader will gain: In an effort to bridge the gaps between existing knowledge and future prospects of drug discovery, we found interesting studies validating drug targets and paving the way for better experiments to be designed. In a few cases, novel pathways have been characterized, while in others, well established pathways when probed further, led to the discovery of new drug targets.

Take home message: The review constitutes a comprehensive report on upcoming drug targets, with emphasis on glycosylphosphatidylinositol (GPI)-anchored glycoconjugates along with related biochemistry of enolase, glycosome and purine salvage pathways, as we strive to bring ourselves a step closer to being able to combat this deadly disease.     

Structure-based drug discovery and protein targets in the CNS

Structure-based methods are having an increasing role and impact in drug discovery. The crystal structures of an increasing number of therapeutic targets are becoming available. These structures can transform our understanding of how these proteins perform their biological function and often provide insights into the molecular basis of disease. In addition, the structures can help the discovery process. Methods such as virtual screening and experimental fragment screening can provide starting hit compounds for a discovery project. Crystal structures of compounds bound to the protein can direct or guide the medicinal chemistry optimisation to improve drug-like properties - not only providing ideas on how to improve binding affinity or selectivity, but also showing where the compound can be modified in attempting to modulate physico-chemical properties and biological efficacy. The majority of drug discovery projects against globular protein targets now use these methods at some stage.This review provides a summary of the range of structure-based drug discovery methods that are in use and surveys the suitability of the methods for targets currently identified for CNS drugs. Until recently, structure-based discovery was difficult or unknown for these targets. The recent determination of the structures of a number of GPCR proteins, together with the steady increase in structures for other membrane proteins, is opening up the possibility for these structure-based methods to find increased use in drug discovery for CNS diseases and conditions.     

Src kinase inhibitors: an emerging therapeutic treatment option for prostate cancer

Importance of the field: Once prostate cancer becomes castration-resistant, bone metastases are a significant problem and treatment options are limited. As a result, there is a need for more effective therapies that have antitumor and anti-bone metastatic effects. Because Src and Src-family kinases (SFKs) are involved in multiple signaling pathways central to prostate cancer development, progression, and metastasis, in addition to normal and pathologic osteoclast activities, Src inhibition represents a valid therapeutic strategy for investigation.

Areas covered in this review: Here, current treatment options for advanced prostate cancer, the preclinical rationale behind using Src inhibitors, emerging data from clinical trials of Src inhibitors in prostate cancer, and future therapeutic directions are described. Data published in peer-reviewed journals within the last 20 years or presented at recent European or American Society of Clinical Oncology conferences have been reviewed.

What the reader will gain: Readers will gain an insight into the development of therapeutic Src inhibitors, including dasatinib and saracatinib; an understanding of their effects on prostate cancer cells and the bone microenvironment; and emerging clinical data.

Take home message: Src is implicated in prostate cancer progression and metastasis, therefore treatment with Src inhibitors warrants further investigation.     

Human kinome drug discovery and the emerging importance of atypical allosteric inhibitors

Importance of the field: Protein kinases are important targets for drug discovery because they possess critical roles in many human diseases. Several protein kinase inhibitors have entered clinical development with others having already been approved for treating a host of diseases. However, many kinase inhibitors suffer from non-selectivity because they interact with the ATP binding region which has similar structures amongst the protein kinases and this non-selectivity sometimes can cause side effects. As a consequence, there is much interest in developing drugs that inhibit kinases through non-classical mechanisms with the hope of avoiding the side effects of previous kinase drugs. Areas covered in this review: This review covers emerging information on kinase biology and discusses new approaches to design selective inhibitors that do not compete with ATP. What the reader will gain: The reader will gain a better understanding of the importance of the field of allosteric inhibitor drug discovery and how this has required the adoption of a new generation of high-throughput screening techniques. Take home message: Discovery and development of allosteric modulators will result in a family of novel kinase therapies with greater selectivity and more varied ways to control activity of disease causing kinase targets.     

COPD: preclinical models and emerging therapeutic targets

ABSTRACT

Introduction: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Preclinical models of COPD have recently been developed. In those models, COPD/emphysema has been commonly induced using different toxic agents such as elastase, proteolytic enzymes and chronic exposure to cigarette smoke (CS).

Areas covered: The most relevant features of preclinical models of COPD, namely chronic exposure to CS and other agents (proteases and microorganisms), cardiovascular effects, surfactant protein-D, airway remodeling and inflammation, lung regeneration potential and mesenchymal stromal cell therapy are described. The most relevant publications on the topic of interest were selected from Pubmed.

Expert opinion: Preclinical models of COPD are key for understanding the underlying biology and pathophysiology of the disease and for the discovery of therapeutic targets. Enhanced biological insights will help discover therapeutic targets for the treatment of COPD. This will enable health caregivers and doctors to improve treatment where a more holistic approach will be used. This will benefit the patients and society because the use of resources should be significantly lowered.     

Metallocarboxypeptidases: emerging drug targets in biomedicine

Metallocarboxypeptidases (MCPs) are commonly regarded as exopeptidases that actively participate in the digestion of proteins and peptides. In the recent years, however, novel MCPs comprising a wide range of physiological roles have been found in different mammalian extra-pancreatic tissues and fluids. Among them, CPU, also known as thrombin-activatable fibrinolysis inhibitor (TAFI), has been shown to cleave C-terminal Lys residues from partially degraded fibrin, acting as inhibitor of clot fibrinolysis and therefore constituting an important drug target for thrombolytic therapies. Other MCPs such as CPE, CPN, CPM, and CPD function as pro-hormone and neuropeptide processors and display several structural differences with the pancreatic-like enzymes. In addition, important advances have been made in the discovery and characterization of new endogenous and exogenous proteinaceous inhibitors; the structural determination of their complexes with several MCPs has revealed novel binding modes. Finally, the use of MCPs in antibody-directed enzyme pro-drug therapy (ADEPT) has proved to be an efficient approach for the delivery of lethal levels of chemotherapeutic drugs specifically at tumor tissues. Taken together, these recent developments may help to understand potential biomedical implications of MCPs. Future perspectives for the regulation of these enzymes through the use of more selective and potent inhibitors are also discussed in this review and combined with earlier observations in the field.     

Matrix metalloproteases: Structure-based drug discovery targets

Summary Matrix metalloproteases (MMPs) are a large family of mammalian zinc-dependent proteases that have garnered much attention as targets for drug discovery. In part, this interest is spurred by the central role these enzymes may play in diseases such as arthritis and cancer. One consequence of this attention has been the rapid accumulation of structure information. The structures of inhibitor-MMP complexes have provided a focus for drug discovery efforts in defining features of the MMP catalytic domain that will be critical in developing potent and selective inhibitors. Inhibitor interactions at the active-site zinc are clearly important in defining the binding mode and relative inhibitor potency. Selective inhibitors will also, most likely, take advantage of the S₁ substrate binding pocket, as there are relatively obvious differences at this site between the various members of the MMP family.     

Binary encoded small-molecule libraries in drug discovery and optimization

Summary A variety of small-molecule combinatorial libraries have been prepared on solid support using a binary encoding strategy employing non-sequenceable encoding molecules. Library members are attached to the support using photolabile linkers which permit their release for assay free in solution. The encoding molecules are attached using a carbene insertion reaction and are released via oxidation. A wide variety of synthetic reactions have been utilized for library synthesis including, for example, cyclocondensations, reductive aminations, and heteroaromatic halide displacements, as well as acylations and sulfonylations. Initial screening of two such libraries identified lead structures for the inhibition of carbonic anhydrase. Subsequently, based upon these leads a smaller focused combinatorial library was constructed and used to analyze the structure-activity relationships (SARs) governing enzyme inhibition and isozyme selectivity. The combination of random screening with a broad diversity of compounds, followed by focused libraries for detailed SARs and selectivity, demonstrates the power of binary encoded small-molecule combinatorial libraries for drug discovery.