This book highlights recent progress in the development of small-molecule inhibitors of oncogenic transcription factors and is relevant for postgraduates, researchers and practitioners.

Transcription is frequently deregulated in cancer, but targeting of transcriptional processes for cancer therapy has thus far been limited to nuclear receptors. Recent studies, however, have suggested that inhibitors of various general transcriptional regulators can be used in cancer therapy because expression of some oncogenes is disproportionately sensitivity to these inhibitors. Here, I describe the cellular and molecular effects of inhibiting a general transcriptional regulator, CDK7, in T-cell acute lymphoblastic leukemia (T-ALL) cells. Because tumor cells commonly evolve resistance to individual therapies, I have also investigated the potentially synergistic effects of combining two compounds that target transcriptional regulators - the CDK7-inhibitor THZ1 and the BRD4-inhibitor JQ1 - and suggest a model describing the molecular basis of the synergistic effects I observed. My research provides insight into the effects of these inhibitors of general transcriptional regulators on tumor cell behavior and gene expression programs.

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.

This volume, which includes contributions from leading scientists and clinicians in the field, provides definitive, state-of-the-art information on STAT inhibitors in a biological and clinical context. It gives an overview of the biology of the STAT family of transcription factors and their role in cancer etiology. Additionally, it describes the raft of therapeutic approaches being used to inhibit STATs in the context of various cancers, covering the full spectrum of therapeutic approaches to inhibiting STATs, and presenting emerging data from clinical trials.

This book systematically reviews the most important findings on cancer immune checkpoints, sharing essential insights into this rapidly evolving yet largely unexplored research topic. The past decade has seen major advances in cancer immune checkpoint therapy, which has demonstrated impressive clinical benefits. The family of checkpoints for mediating cancer immune evasion now includes CTLA-4, PD-1/PD-L1, CD27/CD70, FGL-1/LAG-3, Siglec-15, VISTA (PD-1L)/VSIG3, CD47/SIRPA, APOE/LILRB4, TIGIT, and many others. Despite these strides, most patients do not show lasting remission, and some cancers have been completely resistant to the therapy. The potentially lethal adverse effects of checkpoint blockade represent another major challenge, the mechanisms of which remain poorly understood. Compared to the cancer signaling pathways, such as p53 and Ras, mechanistic studies on immune checkpoint pathways are still in their infancy. To improve the responses to checkpoint blockade therapy and limit the adverse effects, it is essential to understand the molecular regulation of checkpoint molecules in both malignant and healthy cells/tissues. This book begins with an introduction to immune checkpoint therapy and its challenges, and subsequently describes the regulation of checkpoints at different levels. In closing, it discusses recent therapeutic developments based on mechanistic findings, and outlines goals for future translational studies. The book offers a valuable resource for researchers in the cancer immunotherapy field, helping to form a roadmap for checkpoint regulation and develop safer and more effective immunotherapies.