Kinase Inhibitors

The approval of cancer drugs by the United States Food and Drug Administration have increased progressively over the past
two decades with a trend towards the adoption of targeted drugs which are more precise in their mechanisms of action.
Advances in genetic profiling, immunohistochemical analysis of tumors, biomarker development, and a renewed appreciation
of the tumor microenvironment have produced a new generation of targeted chemical and biological therapies. These
innovations are the fruits of basic research in molecular and cellular biology, biochemistry, and immunology.
Purpose: To elucidate the paradigm shift in cancer drug development that has impacted the lives of patients in terms of
quality of life, tumor responses, over-all survival, and potential cures.
Methods: This review is based on an examination of published literature using the National Center for Biotechnology Information
(NCBI), the USFDA/National Institutes of Health (NIH) websites, USFDA approved product literature, Center Watch,
industry-sponsored websites, and clinicaltrials.gov websites. Cancer drugs are classified and described based on their proposed
mechanisms of action.
Results: The last two decades witnessed a paradigm shift in cancer drug development toward molecular targeted therapies
and targeted drug delivery. Molecular targets include tyrosine kinase receptors, serinethreonine kinase signaling pathways,
and growth factors. An increasing number of antibody-based therapies have emerged. Improvements in drug delivery include
the use of albumin-bound nanoparticles for targeting the enhanced permeability and retention effects seen in tumors.
Recent developments in the fields of cancer immunotherapy and gene therapy are exceedingly encouraging.
Conclusions: A review of USFDA-approved drugs and cancer drugs in clinical development, based on their mechanisms of
action, is presented. The progressive shift in cancer drug development towards targeted therapies and cancer immunotherapy
raises hope for improved outcomes for many types of cancer in the future.

JNK is a subfamily of MAP kinases that hat regulates a range of biological processes implicated in response to stress, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock as well as growth factors like PDGF, EGF, FGF, etc. They were originally identified as kinases that bind and phosphorylate JUN on S63 and Se73 within its transcriptional activation domain. The deregulation of these kinases is shown to be involved in human diseases, such as cancer, immune diseases and neurodegenerative disorders. The realization of the therapeutic potential of the inhibition of JNKs led to a thorough search for small-molecule inhibitors first for research purposes, but later also for therapeutic applications. Here, we discuss some of the most well-known JNK inhibitors and their use in basic research or clinical science.

Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the “master IRAK”, the only family member indispensable for IL-1R/TLR signaling. In humans, mutations resulting in IRAK-4 deficiency have been linked to susceptibility to bacterial infections, especially recurrent pyogenic bacterial infections. Furthermore, knock-in experiments by several groups have clearly demonstrated that IRAK-4 requires its kinase activity for its function. Given the critical role of IRAK-4 in inflammatory processes, modulation of IRAK-4 kinase activity presents an attractive therapeutic approach for the treatment of immune and inflammatory diseases. The recent success in the determination of the 3-dimensional structure of the IRAK-4 kinase domain in complex with inhibitors has facilitated the understanding of the mechanistic role of IRAK-4 in immunity and inflammation as well as the development of specific IRAK-4 kinase inhibitors. In this article, we review the biological function of IRAK-4, the structural characteristics of the kinase domain, and the development of small molecule inhibitors targeting the kinase activity. We also review the key pharmacophores required for several classes of inhibitors as well as important features for optimal protein/inhibitor interactions. Lastly, we summarize how these insights can be translated into strategies to develop potent IRAK-4 inhibitors with desired properties as new anti-inflammatory therapeutic agents.

Atypical protein kinase Cs (aPKC) are involved in cell cycle progression, tumorigenesis, cell survival and migration in many cancers. We believe that aPKCs play an important role in cell motility of melanoma by regulating cell signaling pathways and inducing epithelial to mesenchymal transition (EMT). We have investigated the effects of two novel aPKC inhibitors; 2-acetyl-1,3-cyclopentanedione (ACPD) and 3,4-diaminonaphthalene-2,7-disulfonic acid (DNDA) on cell proliferation, apoptosis, migration and invasion of two malignant melanoma cell lines compared to normal melanocytes. Molecular docking data suggested that both inhibitors specifically bind to protein kinase C-zeta (PKC-ζ) and PKC-iota (PKC-ι) and kinase activity assays were carried out to confirm these observations. Both inhibitors decreased the levels of total and phosphorylated PKC-ζ and PKC-ι. Increased levels of E-cadherin, RhoA, PTEN and decreased levels of phosphorylated vimentin, total vimentin, CD44, β-catenin and phosphorylated AKT in inhibitor treated cells. This suggests that inhibition of both PKC-ζ and PKC-ι using ACPD and DNDA downregulates EMT and induces apoptosis in melanoma cells. We also carried out PKC-ι and PKC-ζ directed siRNA treatments to prove the above observations. Immunoprecipitation data suggested an association between PKC-ι and vimentin and PKC-ι siRNA treatments confirmed that PKC-ι activates vimentin by phosphorylation. These results further suggested that PKC-ι is involved in signaling pathways which upregulate EMT and which can be effectively suppressed using ACPD and DNDA. Our results summarize that melanoma cells proliferate via aPKC/AKT/NF-κB mediated pathway while inducing the EMT via PKC-ι/Par6/RhoA pathway. Overall, results show that aPKCs are essential for melanoma progression and metastasis, suggesting that ACPD and DNDA can be effectively used as potential therapeutic drugs for melanoma by inhibiting aPKCs.

Aurora kinases play pivotal role in mitosis. Aurora kinase A controls centrosome
duplication, spindle pole integrity as well as bipolar spindle formation. Aurora kinase B is part of
the chromosome passenger complex (CPC) and through these co-factors it drives chromosome
congression, bidirectional tension on kinetochores and spindle checkpoint signalling as well as
cytokinesis completion.
Both CPC and Aurora kinases are exclusively expressed during mitosis and are upregulated
in many tumours. Their over-expression correlates with the level of genomic instability
within tumours and therefore these proteins are proposed as potential targets for cancer therapy.
This review describes the interplay between Aurora kinases in mitosis and the different
strategies developed towards their targeting.

The cytoplasmatic tyrosine in kinase c-Src is involved in the regulation of several cell functions including adhesion, invasion, proliferation, survival and angiogenesis. Src activity is strictly regulated in healthy cells, whereas its overexpression or hyperactivation plays a critical role during tumor development. Recently it has been suggested that the oncogenic potential of Src is linked to its role in the activation of key signaling molecules involved in several cell pathways, rather than its direct activity. For all these reasons Src represents a promising therapeutic target for the treatment of tumors. In this article a number of examples of c-Src inhibitors appeared in selected patents from 2006 to early 2011 will be reported, focusing on their chemical features and, whenever possible, on structureactivity relationships and mechanism of action. Examples of type I or II ATP-competitive inhibitors or substrate competitive inhibitors will be presented. The research in this field is very active and will probably lead to the discovery of therapeutically useful compounds, both c-Src selective and multitargeted inhibitors, that acting on different cell pathways could be more effective in blocking cancer development. However, only the results of clinical trials will show in the near future the most promising compounds.