Most biological processes including signal transduction via transcription factors are mediated through protein-protein interactions (PPIs). Deregulations of the proteins involved in these interactions have been implicated in contributing to disease progression. It is now well established that cancer can be the result of aberrant PPIs, either through the loss of an essential interaction or, through the overactivation of transcription factors. Thus, targeting transcription factors have become attractive molecular targets. The multi-faceted approach to medicinal chemistry that encompasses synthesis, computational analyses, biophysical and biological evaluations are demonstrated by the invention and production of small molecule inhibitors for two well-known protein targets, the transcription factor STAT5 and the ubiquitin E3 ligase MDM2. A structure based drug design (SBDD) strategy was utilized in the discovery of the first potent and selective inhibitor of the STAT5 protein with optimal metabolic stability. Throughout our efforts in establishing an inhibitor for STAT5, we investigated STAT5 isoforms and their roles in driving several malignancies within the body. A novel STAT5A isoform FP assay was developed and efforts were undertaken to identify an isoform selective inhibitor. A STAT5B selective compound was identified with similar potencies to our first generation lead 13a. With a newly discovered pharmacophore for STAT5, optimizations of the tripodal scaffold were carried out to reduce entropic costs to binding. A new class of benzodiazepines were produced, however, these compounds did not result in a favorable potency/selectivity profile for the STAT5 protein. The class of benzodiazepines was then reevaluated for the MDM2 target with promising preliminary in vitro evaluations. We have identified the first in class and best in class inhibitor for the STAT5 protein reported to date. With a favorable potency/selectivity profile and optimal metabolic stability, two lead compounds have the potential to become candidates for advanced preclinical trials as a STAT5-targeted therapeutic. In addition, these small molecule inhibitors can serve as research tools to investigate the knockdown of STAT5 function at the protein level.

Oncogenic transcription factors are an increasingly important target for anticancer therapies. Inhibiting these transcription factors could allow tumour cells to be "reprogrammed", leading to apoptosis or differentiation from the malignant phenotype. As the use of kinase inhibitors is gradually declining, transcription factor inhibition is the next hot topic for oncology research and merits much attention. This book highlights recent progress in the development of small-molecule inhibitors of oncogenic transcription factors. It also presents the evidence that this important protein class can be modulated in a number of ways to develop novel classes of therapeutic agents. The broad range of aspects covered by the book is noteworthy and renders it enormously valuable. This title serves as a unique reference book for postgraduates, academic researchers and practitioners working in the fields of biochemistry, biotechnology, cell and molecular biology and bio-inorganic chemistry.

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.

This book provides a comprehensive and up-to-date review of all aspects of childhood Acute Lymphoblastic Leukemia, from basic biology to supportive care. It offers new insights into the genetic pre-disposition to the condition and discusses how response to early therapy and its basic biology are utilized to develop new prognostic stratification systems and target therapy. Readers will learn about current treatment and outcomes, such as immunotherapy and targeted therapy approaches. Supportive care and management of the condition in resource poor countries are also discussed in detail. This is an indispensable guide for research and laboratory scientists, pediatric hematologists as well as specialist nurses involved in the care of childhood leukemia.

Breaking Tolerance to Pancreatic Cancer Unresponsiveness to Chemotherapy edited by Dr. Nagaraju, PhD., DSc. focuses on overriding the resistance from chemotherapeutic drugs with a broader range of treatment options. It particularly focuses on stroma, tumor microenvironment, stem cells, stellate cells, transcription factors, growth factors, and important signaling pathways. This volume discusses topics such as pancreatic cancer biology, current therapeutic options, EMT, chemotherapy resistance mechanisms, and genetic manipulations and natural products to enhance the sensitivity of pancreatic cancer to chemotherapy. Additionally, it discusses small targeted molecules and pancreatic cancer trials, and nanotechnology-based drug delivery. Breaking Tolerance to Pancreatic Cancer Unresponsiveness to Chemotherapy is a valuable source for researchers and advanced students in cancer and oncology as well as clinicians and medical students who are interested in learning more about ways to break pancreatic cancer resistance to chemotherapy. Modulates the biologic properties of stroma in pancreatic cancer by targeting the several chemotherapy resistance mechanisms to impede their malignant property by introducing new strategies and drugs Provides information about on-going research as well as clinical data on pancreatic cancer and detailed descriptions about therapeutic options for easy understanding Utilizes full color figures to help the understanding of the content and tables for easy comparison of information as well as quick access to it

This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.

One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."

This book is a state-of-the-art summary of the latest achievements in cell cycle control research with an outlook on the effect of these findings on cancer research. The chapters are written by internationally leading experts in the field. They provide an updated view on how the cell cycle is regulated in vivo, and about the involvement of cell cycle regulators in cancer.

Kinase drug discovery remains an area of significant interest across academia and in the pharmaceutical industry. There are now around 13 FDA approved small molecule drugs which target kinases and many more compounds in various stages of clinical development. Although there have been a number of reviews/publications on kinase research, this book fills a gap in the literature by considering the current and future opportunities and challenges in targeting this important family of enzymes. The book is forward-looking and identifies a number of hot topics and key areas for kinase drug discovery over the coming years. It includes contributions from highly respected authors with a combined experience in the industry of well over 200 years, which has resulted in a book of great interest to the kinase field and across drug discovery more generally. Readers will gain a real insight into the huge challenges and opportunities which this target class has presented drug discovery scientists. The many chapters cover a wide breadth of topics, are well written and include high quality colour and black and white images. Topics covered include an outline of how medicinal chemistry has been able to specifically exploit this unique target class, along with reflections on the mechanisms of kinases inhibitors. Also covered is resistance to kinase inhibitors caused by amino acid mutations, case studies of kinase programs and reviews areas beyond protein kinases and beyond the human kinome. Also described are modern approaches to finding kinase leads and the book finishes with a reflection of how kinase drug discovery may progress over the coming years.

This is the third volume in the new World Health Organization series on histological and genetic typing of tumours. Tumours of the haematopoietic and lymphoid tissues are covered. This was a collaborative project of the European Association for Haematolpathology and the Society for Haematopathology and others. The WHO classification is based on the principles defined in the Revised European-American Classification of Lymphoid Neoplasms (REAL) classification. Over 50 pathologists from around the world were involved in the project and proponents of all major lymphoma and leukaemia classifications have agreed to accept the WHO as the standard classification of haematological malignancies. So this classification represents the first true world wide concensus of haematologic malignancies. Colour photographs, magnetic resonance and ultrasound images and CT scans are included.