Current Pharmaceutical Design - Volume 23, Issue 29, 2017

Over the last three decades, neoplasms have become the largest cause of human mortality due to both high tumor incidence and mortality. Chemotherapy is one of the main therapies employed to treat neoplasms. Although classical genotoxic drugs, such as cyclophosphamide, 5-FU, cisplatin and doxorubicin have been applied in clinical settings and have achieved very good treatment efficacy, many cancer patients died of tumor metastasis, drug toxicity or drug resistance due to tumor heterogeneity. Targeted molecular treatments based on the genes, receptors, and kinases expressed by a tumor make individualized treatment possible. Protein kinases catalyze the phosphorylation of proteins and are involved in multiple cellular processes. In many cancers, mutation or abnormal expression of protein kinases is correlated with tumorigenesis, metastasis and resistance to chemotherapy. Tumor-related protein kinases have become important molecular targets and biomarkers. The use of protein kinases as tumor biomarkers primarily focuses on tyrosine and serine/threonine kinases. Many tumor drugs targeting protein kinases, such as monoclonal antibody and tyrosine kinase inhibitors (TKIs), are widely utilized in clinic. Additional drugs aimed at combating drug resistance and metastasis should be developed targeting protein kinases. In this review, we summarize several important protein kinases involved in cancer and analyze why these kinases can be used as biomarkers or targets for cancer diagnosis and/or treatment. Furthermore, numerous drugs targeting protein kinases as well as their development and activity are discussed.

Protein tyrosine phosphorylation is a crucial signaling mechanism that plays a role in epithelial carcinogenesis. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, metabolism, and motility by activating major signaling pathways including STAT3, AKT, and MAPK. Genetic mutation of PTKs and/or prolonged activation of PTKs and their downstream pathways can lead to the development of epithelial cancer. Therefore, PTKs became an attractive target for cancer prevention. PTK inhibitors are continuously being developed, and they are currently used for the treatment of cancers that show a high expression of PTKs. Protein tyrosine phosphatases (PTPs), the homeostatic counterpart of PTKs, negatively regulate the rate and duration of phosphotyrosine signaling. PTPs initially were considered to be only housekeeping enzymes with low specificity. However, recent studies have demonstrated that PTPs can function as either tumor suppressors or tumor promoters, depending on their target substrates. Together, both PTK and PTP signal transduction pathways are potential therapeutic targets for cancer prevention and treatment.

Accumulating studies have provided concrete evidence that p90 ribosomal S6 kinase 2 (RSK2) is a key signaling molecule involved in cell proliferation, transformation, and cancer development. RSK2 is known to be an etiological gene of Coffin-Lowry Syndrome (CLS). Recently, signaling analysis and molecular biological approaches have provided concrete evidence that RSK2 plays an essential role in human cancers. Here, we will extensively discuss signaling pathways regulating RSK2 activity, the role of RSK2 in human cancer development, inhibitors suppressing RSK2 activity, and why RSK2 is an important target to develop drugs for human cancers.

Phosphorylation, the addition of a phosphate group to a molecule, is an effective way of regulating the biological properties of that molecule. Protein phosphorylation is a post-translational modification of proteins and affects cellular signaling transduction. Protein kinases induce phosphorylation by catalyzing the transfer of phosphate groups to serine, threonine, and tyrosine residues on protein substrates. Consistent with their roles in cancer, protein kinases have emerged as one of the most clinically useful target molecules in pharmacological cancer therapy. Intrinsic or acquired resistance of cancers against anti-cancer therapeutics, such as ionizing radiation, is a major obstacle for the effective treatment of many cancers. In this review, we describe key aspects of various kinases acting on proteins. We also discuss the roles of protein kinases in the pathophysiology and treatment of cancer. Because protein kinases correlate with radiation resistance in various types of cancer, we focus on several kinases responsible for radiation resistance and/or sensitivity and their therapeutic implications. Finally, we suggest some ongoing radiation-sensitization strategies using genetic loss and/or kinase inhibitors that can counteract radiation resistance-related protein kinases.

Protein kinases are enzymes that catalyze the transfer of phosphate from ATP to the serine/threonine or tyrosine residues of target molecules. These are key important mediators in a signaling cascade involved in several biological processes. Dysregulation of their activity has been found in various tumors. From the increased understanding of kinase structure and activation mechanisms emerged new strategies for targeting kinase in cancer treatment. Nowadays, kinase specific inhibitors are developed and widely used for clinical cancer treatment. In this review, we focus on protein kinases that are involved in cholangiocarcinoma (CCA). CCA is a slow progression tumor that is recognized as a major public health issue in northeastern Thailand. The standard regimen for CCA treatment is surgical resection. However, the patient's clinical outcome is still problematic. Therefore, the search to identify molecular mechanisms and molecules that are involved in carcinogenesis and the progression of CCA that can be used as therapeutic targets is urgently required. Aberrant expression and activation, as well as the functions of protein kinases in CCA, have been extensively studied in order to apply them as therapeutic targets. This review provides the information on protein kinases and their activity in CCA, as well as the preclinical data on kinase inhibitors that have been evaluated for this cancer.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults with intensive heterogeneity and one of the most lethal human cancers. Protein kinases control diverse cellular processes by coordinating different signaling pathways. Protein kinases are frequently dysregulated in human cancers, which contributes to tumor initiation and development. Thus, protein kinases are a growing drug target class for cancers including glioblastoma. This review focuses on the most important protein kinases and kinase-mediated signaling cascades in glioblastoma, and discusses the functional mechanism of these kinases in glioblastoma tumorigenesis. Moreover, this review has summarized the most recent preclinical and clinical advances of agents targeting protein kinases in the treatment of glioblastoma.

Acute myeloid leukemia (AML) is a malignant blood disorder and the cure rate has been remarkably improved over the past decade. However, recurrent or refractory leukemia remains the major problem of the AML and no clearly effective therapy has been established so far. Traditional treatments such as chemotherapy and hematopoietic stem cell transplantation are both far dissatisfying the patients partly for their individual variety. Besides, conventional treatments usually have many side effects to result in poor prognosis. Therefore, an urgent need is necessary to update therapies of AML. To date, protein kinase inhibitors as new drugs offer hope for AML treatment and many of them are on clinical trials. Here, this review will provide a brief summary of protein kinase inhibitors investigated in AML thus far, mainly including tyrosine protein kinase inhibitors and serine/threonine kinase inhibitors. We also presented the sketch of signal pathways involving protein kinase inhibitors, as well as discussed the clinical applications and the challenges of inhibitors in AML treatment.

Despite the breakthroughs that have been achieved, significant unmet needs relating to the inadequate efficacy and toxicity of currently-available cancer therapies remain. Kinase inhibitors are a class of agents that target signaling factors responsible for the survival of malignant cells, and may address at least some of these issues. The concept of synthetic lethality provides a potential solution to counteract pathway redundancies, and refers to situations in which a mutation in one of two particular genes alone permits cell survival, while simultaneous mutation in both results in cell death. When exploited in the context of cancer therapy, pathways that are uniquely upregulated in cancer cells become selective targets, with reduced off-target toxicity toward their healthy counterparts. Natural compounds represent a large and readily-accessible library of bioactive structures that can be screened for synthetically lethal interactions by testing for the inhibition of kinases relevant to cancer cell survival. In this review, we discuss the concept of synthetic lethality and focus on scenarios in which natural compounds that target kinases may be applied to tip the balance in favor of cancer cell death during therapeutic challenge.

The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism, and angiogenesis. This protein is an attractive target for new anticancer drug development. Significant progress has been made in hit discovery, lead optimization, drug candidate development and determination of the three-dimensional (3D) structure of mTOR. Computational methods have been applied to accelerate the discovery and development of mTOR inhibitors helping to model the structure of mTOR, screen compound databases, uncover structure-activity relationship (SAR) and optimize the hits, mine the privileged fragments and design focused libraries. Besides, computational approaches were also applied to study protein-ligand interactions mechanisms and in natural product-driven drug discovery. Herein, we survey the most recent progress on the application of computational approaches to advance the discovery and development of compounds targeting mTOR. Future directions in the discovery of new mTOR inhibitors using computational methods are also discussed.

GSK3 has gained a considerable attention of researchers in the late 1970s as an inevitable drug target to treat diabetes. Furthermore, it was found to have a key role in the development of diseases like cancer and neurodegeneration (ND). A broad spectrum of GSK3 inhibitors have been discovered from time to time in order to curb these diseases. Inhibition of GSK3 by insulin boosts the dephosphorylation of glycogen synthase, hence its activation to convert UDP glucose into glycogen. Lack of insulin and insulin-resistance is supposed to be the cause of type 2 diabetes (Diabetes mellitus). Additionally, GSK3 stabilizes the components of beta-catenin complex, hence promotes oncogenesis. Phosphorylation of GSK3 by Akt and some other kinases also favours the carcinogenesis. However, in some cases GSK3 has tumor supressing character. GSK3 has been found to have a prominent role in the formation of amyloid plaques and neurofibrillary tangles (abnormal protein accumulations) which are the main suspects of Alzheimer's disease (AD). GSK3 inhibitors have been reported to have amyloidbeta disaggregation property and have been found to promote the adult hippocampal neurogenesis in vivo as well as in vitro. This manuscript thoroughly reviews the involvement of GSK3 in diabetes, cancer and ND. Furthermore, development of GSK3 inhibitors as antidiabetes, anticancer and antineurodegenerative agents focusing mainly on lead optimization has been discussed.

Protein phosphorylation, mediated by protein kinases, has important physiological and pathological implications in our lives. Targeting kinase is one of the most interesting of the emerging topics in the pharmaceutical industry, especially since there is a focus on cancer therapy. Given that kinases may be involved in the aging process the focus will be on using the kinase inhibitor for anti-aging intervention to enhance healthspan and increase longevity. In this review, we will summarize: (i) the impact of the phosphoproteomic approach to elucidate molecular mechanisms of diseases; (ii) importance of the drug discovery approach for targeting kinases; (iii) the dysregulation of Janus kinase (JAK) / signal-transducing adapter molecules (STAT) and p70 ribosomal protein S6 kinase (S6Ks) pathway in aging and the age-related process; (iv) the epidemiological studies available in order to see whether a correlation between JAK/STAT and S6Ks mRNA expression levels exist in cancer and in patient outcome; (v) finally, we will show selected inhibitors of these kinases approved by the US Food and Drug Administration (FDA).

Infectious diseases that are caused by pathogenic microbes such as bacteria, viruses, parasites or fungi remain the top major cause of death across the world, particularly in low income countries, and may be transmitted from person to person, or from insects or animals. In general, infectious diseases may be treated with antimicrobial agents including antibiotics, antiviral, antifungal or antiparasitic medications. The therapeutic application of antimicrobial drugs in the 20th century substantially contributed to the global control of infectious diseases worldwide. However, pathogenic microbes have evolved various mechanisms to render the antimicrobial drugs less effective. This has resulted in an increasing number of people infected with pathogenic microbes that are resistant to antimicrobial drugs, and in some cases leading to untreatable infections. Therefore, new antimicrobial drugs are urgently needed to prevent possible recurrence and emergence of previously treatable infectious diseases. In the past decades, protein kinase inhibitors have become an attractive area in the development of novel antimicrobial drugs. In the current review, we will describe the recent efforts in the development of microbial and host protein kinase-targeting inhibitors as potential antimicrobial drugs against HIV, tuberculosis and malaria.

G protein-coupled receptors (GPCRs), especially the class A, are the most heavily investigated drug targets in the pharmaceutical industry. Tremendous efforts have been made by both industry and academia to understand the molecular structure and function of this large family of transmembrane proteins. Our understanding in GPCR activation has evolved from the classical inactive-active two-state model to a complex view of GPCR conformational ensemble associated with multiple interacting partners such as ligands, allosteric modulators, ions and downstream signaling proteins. New drug targets and ligand design strategies are unveiled. Meanwhile, breakthroughs in X-ray crystallography have resulted in high-resolution structures of over 30 GPCRs, providing structural basis for drug design and functional studies. These enabled wide applications of computational approaches in GPCR research that have led to several groundbreaking studies in the last few years. While a large fraction of human GPCRs has yet to be crystallized, homology modeling plays a pivotal role in the simulation of these GPCRs. Here, we review the recent updates on class A GPCR structure and function, with a focus on the applications and perspectives of molecular modeling in GPCR ligand design.

CD147 is a membrane protein belonging to immunoglobulin superfamily and expressed in the cell membrane, which is also named with an extracellular matrix metalloproteinase inducer (EMMPRIN) because this molecule induces adjacent fibroblasts or tumor cells to produce MMPs, facilitating tumor cells migration and invasion. Accumulating evidences have shown that CD147 is over-expressed in various tumors, including melanoma, liver cancer, and lung cancer, and orchestrates tumor cell proliferation, apoptosis, invasion and metastasis, multidrug resistance and glycolysis through critical molecules such as MMPs, MCTs, Caveolin-1, and VEGF. In this review, we focus on understanding the characteristics of CD147 in various biological functions, including physiological and pathological processes. Recent novel studies have shown that CD147 is not only a potential diagnostic marker but also a therapeutic target for chemotherapy or the diagnosis of cancer.

Pin1 is a unique peptidyl-prolyl cis/trans isomerase (PPIase) that catalyzes the cis/trans isomerization of peptidyl-prolyl peptide bonds of its substrate proteins by binding to their specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs. This alters the conformation of target proteins and consequently affects their stability, intracellular localization, and/or biological functions. The abnormal overexpression of Pin1 is observed in some malignancies, which is associated with cancer cell proliferation, migration and invasion. However, a role for Pin1 as a putative tumor suppressor has recently been suggested. Systematic dissection of pro-oncogenic vs. tumor suppressive functions of Pin1 will be necessary.