The constitutive activation of Stat3 is frequently detected in human breast cancer cell lines as well as in clinical breast cancer specimens and may play an important role in oncogenesis of breast carcinoma. Activated Stat3 may participate in oncogenesis by stimulating cell proliferation, promoting tumor angiogenesis, and resisting to apoptosis. Hence, Stat3 represents an attractive target for cancer therapy. In this study, of the nearly 429,000 compounds screened by virtual database screening, chemical samples of top 100 compounds identified as candidate small molecule inhibitors of Stat3 were evaluated using Stat3-dependent luciferase reporter as well as other cell-based assays. Through serial functional evaluation based on our established cell-based assays, one compound, termed Sta-21 inhibits Stat3 DNA binding activity, Stat3 dimerization, and Stat3-dependent luciferase activity. Moreover, Sta-21 reduces the survival of breast carcinoma cells with constitutive Stat3 signaling but has minimal effect on the cells in which constitutive Stat3 signaling is absent. Together, these results demonstrate that Sta-21 inhibits breast cancer cells that express constitutive active Stat3. Sta-21 may have a therapeutic potential to be developed as a new class of anti-cancer drug for the treatment of human cancer with activated Stat3.

Anti-cancer drug discovery targeting the signal transducer and activator of transcription 3 (STAT3), has been active for more than a decade following a finding that aberrant activity of this transcription factor is involved in more than 70% of cancers. There are two main approaches to directly abating STAT3 activity, one is to inhibit STAT3 homo-dimersation by targeting the SH2 or transcriptional activation domains, and the other is to prevent STAT3 from interacting with DNA targeting its DNA-binding domain (DBD). The aims of this project are to discover novel STAT3 DBD inhibitors for further development and to develop a biophysical assay for the evaluation of STAT3 DBD inhibitors. The foundation to this project involved an observation that a small molecule fragment derived from the STAT3 dimerisation inhibitor BP-1 -102 occupied a site adjacent to the DBD when co-crystallised with a STAT3 (127-688) construct. Consequently, a series of small-molecule fragments were designed based upon the BP-1 -102 fragment. The compounds were synthesised, characterised and biologically evaluated in an attempt to understand the structure-activity relationships (SARs) associated with BP-1 -102. It was anticipated that by modifying the BP-1 -102 structure, the mode of action would be shifted from inhibition of STAT3 dimerisation to blocking STAT3 DNA-binding. However, the small-molecule fragments that were synthesised did not show significantly improved binding affinity compared to the BP-1 -102 fragment. Details of a STAT3 DBD inhibitor, inS3-54, were disclosed in 2014 and 2016, so the focus of the project shifted towards modifying this new inhibitor scaffold. A series of novel STAT3 DBD inhibitors were designed and docked in silico, then synthesised and biologically tested in vitro. Due to the lack of cell-free assays for evaluating STAT3 DBD inhibitors, a new orthogonal fluorescence polarisation (FP) assay was developed and validated to assess ligand binding. The preliminary results suggest some of the new structures are able to inhibit STAT3 DNA-binding in this FP assay after 24 hr incubation. Such compounds are potential lead structures for further development as STAT3 inhibitors.

With the critical role of aberrantly active Signal Transducer and Activator of Transcription (Stat) 3 protein in many human cancers, selective small-molecule inhibitors targeting the dimerization event which is required for stat3 activation, would be valuable as therapeutic agents. And the inhibitors will be useful chemical probes to clarify the complex biological functions of Stat3. By computational and structural analyses of the interaction between Stat3 and the lead dimerization disruptor, S3I-201, we have designed a diverse set of analogs. One of the most active analogs, S3I-201.1066 is derived to contain a cyclo-hexyl benzyl moiety on the amide nitrogen, which increases the binding to the Stat3 SH2 domain. Evidence is presented from in vitro biochemical and biophysical studies that S3I-201.1066 directly interacts with Stat3 or the SH2 domain, with an affinity (K[subscript D]) of 2.74 [micrometer], and disrupts the binding of Stat3 to the cognate pTyr-peptide, GpYLPQTV-NH2, with an IC50 of 23 [micrometer]. Moreover, S3I-201.1066 selectively blocks the association of Stat3 with the epidermal growth factor receptor (EGFR), and inhibits Stat3 tyrosine phosphorylation and nuclear translocation in EGF-stimulated mouse fibroblasts. In cancer cells that harbor aberrant Stat3 activity, S3I-201.1066 inhibits constitutive Stat3 DNA-binding and transcriptional activities.

This book presents an overview of antimicrobial peptides (AMPs), their mechanisms of antimicrobial action, other activities, and various problems that must still be overcome regarding their clinical application. Divided into four major parts, the book begins with a general overview of AMPs (Part I), and subsequently discusses the various mechanisms of antimicrobial action and methods for researching them (Part 2). It then addresses a range of activities other than antimicrobial action, such as cell penetration, antisepsis, anticancer, and immunomodulatory activities (Part 3), and explores the prospects of clinical application from various standpoints such as the selective toxicity, design, and discovery of AMPs (Part 4). A huge number of AMPs have been discovered in plants, insects, and vertebrates including humans, and constitute host defense systems against invading pathogenic microorganisms. Consequently, many attempts have been made to utilize AMPs as antibiotics. AMPs could help to solve the urgent problem of drug-resistant bacteria, and are also promising with regard to sepsis and cancer therapy. Gathering a wealth of information, this book will be a bible for all those seeking to develop antibiotics, anti-sepsis, or anticancer agents based on AMPs.

Heat shock proteins are emerging as important molecules in the development of cancer and as key targets in cancer therapy. These proteins enhance the growth of cancer cells and protect tumors from treatments such as drugs or surgery. However, new drugs have recently been developed particularly those targeting heat shock protein 90. As heat shock protein 90 functions to stabilize many of the oncogenes and growth promoting proteins in cancer cells, such drugs have broad specificity in many types of cancer cell and offer the possibility of evading the development of resistance through point mutation or use of compensatory pathways. Heat shock proteins have a further property that makes them tempting targets in cancer immunotherapy. These proteins have the ability to induce an inflammatory response when released in tumors and to carry tumor antigens to antigen presenting cells. They have thus become important components of anticancer vaccines. Overall, heat shock proteins are important new targets in molecular cancer therapy and can be approached in a number of contrasting approaches to therapy.

AKT/PKB is a serine/threonine kinase. Inappropriate activation of P13/AKT has been associated with the development of cancer cells, their metastasis and drug resistance. Hence, potent and selective inhibitors targeting AKT are potentially promising drug candidates for the treatment of cancer cells with high-levels of AKT activity. We used a bioinformatics approach to search for AKT inhibitors, based on the correlation analysis between phosphor-Serine 473- AKT or PTEN expression level and the antiproliferation data of NCI small molecule compounds against NCI 60 cancer cell lines, then the candidate compounds were subject to AKT kinase assay. One lead compound API-59 was identified. API- 59 inhibit only AKT activity, does not inhibit phosphor-specific MAP kinase or PT 3 kinase. API-59 also inhibits heregulin-induced AKT activity in MCF-7 breast cancer cells. The AKT inhibitory effect of API-59 can be reversed by increased concentration of ATP. API-59 inhibits the cell proliferation, and induces apoptosis of MDA-453 breast cancer cells with high-levels of AKT activity, only shows a minimal activity in wild-type NIH-3T3 cells that do not overexpress AKT. These data suggest our bioinformatics-based approach is effective in discovery of potent and selective small molecule inhibitors that block AKT kinase activity.

This book is the third volume on this subject and focuses on the recent advances of nanopharmaceuticals in cancer, dental, dermal and drug delivery applications and presents their safety, toxicity and therapeutic efficacy. The book also includes the transport phenomenon of nanomaterials and important pathways for drug delivery applications. It goes on to explain the toxicity of nanoparticles to different physiological systems and methods used to assess this for different organ systems using examples of in vivo systems.

The PI3Ks control many key functions in immune cells. PI3Ks phosphorylate PtdIns(4,5)P2 to yield PtdIns(3,4,5)P3. Initially, PI3K inhibitors such as Wortmannin, LY294002 and Rapamycin were used to establish a central role for Pi3K pathway in immune cells. Considerable progress in understanding the role of this pathway in cells of the immune system has been made in recent years, starting with analysis of various PI3K and Pten knockout mice and subsequently mTOR and Foxo knockout mice. Together, these experiments have revealed how PI3Ks control B cell and T cell development, T helper cell differentiation, regulatory T cell development and function, B cell and T cell trafficking, immunoglobulin class switching and much, much more. The PI3Kd inhibitor idelalisib has recently been approved for the treatment of B cell lymphoma. Clinical trials of other PI3K inhibitors in autoimmune and inflammatory diseases are also in progress. This is an opportune time to consider a Research Topic considering when what we have learned about the PI3K signalling module in lymphocyte biology and how this is making an impact on clinical immunology and haematology.

Billions of dollars are spent every year on research into targeted therapies for cancer. That’s why it’s more than ever crucial for the thousands of scientists working in the field to keep right up to date with the cutting edge. This fascinating collection of material goes a long way to helping them do so, featuring as it does contributions to a crucial international meeting in Italy. The meeting provided a forum for scientists and clinicians working in cancer drug discovery and therapy to share their opinions and experiences. The text here offers readers an overview of diverse approaches, ranging from drug discovery to cellular therapy. Overall, the book addresses the key question of whether ultimately targeted therapy in cancer will be a myth or a reality.

Protein-protein interactions (PPI) are at the heart of the majority of cellular processes, and are frequently dysregulated or usurped in disease. Given this central role, the inhibition of PPIs has been of significant interest as a means of treating a wide variety of diseases. However, there are inherent challenges in developing molecules capable of disrupting the relatively featureless and large interfacial areas involved. Despite this, there have been a number of successes in this field in recent years using both traditional drug discovery approaches and innovative, interdisciplinary strategies using novel chemical scaffolds. This book comprehensively covers the various aspects of PPI inhibition, encompassing small molecules, peptidomimetics, cyclic peptides, stapled peptides and macrocycles. Illustrated throughout with successful case studies, this book provides a holistic, cutting-edge view of the subject area and is ideal for chemical biologists and medicinal chemists interested in developing PPI inhibitors.