Download or read book Small Molecule Transcription Factor Inhibitors in Oncology written by Khondaker Miraz Rahman and published by Royal Society of Chemistry. This book was released on 2018-09-06 with total page 214 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book highlights recent progress in the development of small-molecule inhibitors of oncogenic transcription factors and is relevant for postgraduates, researchers and practitioners.

Download or read book Small Molecule Microarrays Methods and Protocols written by Mahesh Uttamchandani and published by Methods in Molecular Biology. This book was released on 2018-12-05 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Small molecule Inhibition of General Transcriptional Regulators in Cancer written by Jessica Reddy and published by . This book was released on 2016 with total page 155 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book The Design Development of Small Molecule Inhibitors Targeting Unregulated Transcription Factors in Acute Myeloid Leukemia written by Abbarna Anna Cumaraswamy and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Small molecule Transcription Factor Inhibitors in Oncology written by Khondaker Miraz Rahman and published by Royal Society of Chemistry. This book was released on 2018-09-05 with total page 214 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book STAT Inhibitors in Cancer written by Alister C. Ward and published by Springer. This book was released on 2016-10-08 with total page 199 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Regulation of Cancer Immune Checkpoints written by and published by . This book was released on 2020 with total page 657 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book ETS FAMILY OF TRANSCRIPTION FACTORS AS A THERAPEUTIC TARGET IN CANCER written by Tsion Zewdu Minas and published by . This book was released on 2016 with total page 298 pages. Available in PDF, EPUB and Kindle. Book excerpt: The ETS family of transcription factors share a conserved DNA binding domain that recognizes a purine rich consensus sequence with GGAA/T motif. ETS genes have been implicated in a wide array of malignancies including acute myeloid leukemia, Ewing sarcoma and prostate cancer. These genes are suppressed in most adult tissues, while in cancer; their expression is upregulated as a result of chromosomal rearrangements that leave the factors under a control of ubiquitously active promoters. In Ewing sarcoma (ES) patients, tumor specific chromosomal translocation involving FLI1 creates EWS-FLI1 protein. In previous studies, we identified a small molecule inhibitor, YK-4-279, that directly binds to EWS-FLI1 and inhibit its activities. Due to lack of an ES transgenic mouse model, we tested the in vivo therapeutic efficacy of YK-4-279 in the only available transgenic mouse model with EWS-FLI1 induced neoplasm. We showed that short-term YK-4-279 treatment led to correction of abnormal hematopoiesis and improved overall survival of EWS-FLI1+ leukemic mice. Thus far, a genetically engineered mouse model for EWS-FLI1 driven Ewing sarcoma has not been successfully generated. Here, we present data where we tried various approaches to conditionally express EWS-FLI1 using cre recombinase in order to generate a Ewing sarcoma transgenic mouse model. We used the Osx promoter to target Cre recombinase expression to the osteoblast lineage. Alternatively, we injected Cre expressing adenovirus to induce EWS-FLI1 expression locally. Most attempts resulted in embryonic lethality or developmental defects. Chromosomal translocations that involve members of the ETS transcription factor family are also present in a majority of prostate cancer patients. In order to understand how ETS transcription factors drive tumorigenicity in prostate cancer, we investigated their interacting protein partners. We identified and validated ezrin, RHA, and PARP as ERG interacting partners and show that YK-4-279 can inhibit these interactions. Overall, in this study, we demonstrate that direct targeting of ETS transcription factors with small molecules could be of significant therapeutic value in oncology.

Download or read book Developing Small Molecule Inhibitors for P21 to Pave the Way for Novel Therapeutic Approaches for Breast Cancer and Other Cancers written by Tanya A. Zeigler and published by . This book was released on 2008 with total page 144 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book RUNX Proteins in Development and Cancer written by Yoram Groner and published by Springer. This book was released on 2017-03-15 with total page 518 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume provides the reader with an overview of the diverse functions of the RUNX family of genes. As highlighted in the introduction and several of the 29 chapters, humans and other mammals have three RUNX genes that are known to play specific roles in blood, bone and neuronal development. However, their evolutionary history has recently been traced back to unicellular organisms and their involvement in many well-known signaling pathways (Wnt, TGFb, Notch, Hippo) is indicative of a more general function in cell biology. Their documented roles in cell fate decisions include control of proliferation, differentiation, survival, senescence and autophagy. The pleiotropic effects of RUNX in development are mirrored in cancer, where RUNX genes can function as oncogenes that collaborate strongly with Myc family oncogenes or as tumour suppressor genes. In the latter role, they display hallmarks of both ‘gatekeepers’ that modulate p53 responses and ‘caretakers’ that protect the genome from DNA damage. Several chapters focus on the importance of these genes in leukemia research, where RUNX1 and CBFB are frequently affected by chromosomal translocations that generate fusion oncoproteins, while recent studies suggest wider roles for RUNX modulation in solid cancers. Moreover, RUNX genes are intimately involved in the development and regulation of the immune system, while emerging evidence suggests a role in innate immunity to infectious agents, including HIV. At the biochemical level, the RUNX family can serve as activators or repressors of transcription and as stable mediators of epigenetic memory through mitosis. Not surprisingly, RUNX activity is controlled at multiple levels, this includes miRNAs and a plethora of post-translational modifications. Several chapters highlight the interplay between the three mammalian RUNX genes, where cross-talk and partial functional redundancies are evident. Finally, structural analysis of the RUNX/CBFB interaction has led to the development of small molecule inhibitors that provide exciting new tools to decipher the roles of RUNX in development and as targets for therapy. This volume provides a compendium and reference source that will be of broad interest to cancer researchers, developmental biologists and immunologists.

Download or read book The Development of Novel Small Molecule Inhibitors of the Phosphoinositide 3 Kinase Pathway Through High Throughput Cell Based Screens written by and published by . This book was released on 2007 with total page 40 pages. Available in PDF, EPUB and Kindle. Book excerpt: The PTEN/MMAC/TEP-1 tumor suppressor gene (hereafter referred to as PTEN) is a target of somatic mutation in prostate cancer as well as in endometrial cancer, glioblastoma and melanoma (reviewed in (Sansal and Sellers, 2004)) Biallelic loss of PTEN has been demonstrated in both primary and metastatic prostate tumors (reviewed in (Sansal and Sellers, 2004)). In metastatic disease, PTEN loss approaches 50%-60% (Suzuki et al., 1998). Together, these data suggest that loss of PTEN is an important step for those prostate tumors associated with a lethal outcome. Moreover, the loss of PTEN has been intimately linked to deregulation of the PI3K pathway connecting growth and survival signals both to the regulation of the mTOR kinase as well as to the regulation of the FOXO transcription factors. A significant effort is now being expended in the pharmaceutical industry in trying to develop regulators of the PI3K pathway (or more specifically inhibitors) that can reverse the molecular consequences of PTEN loss.

Download or read book The Design Synthesis and Evaluation of Small molecule Inhibitors of Signal Transducer and Activator of Transcription 3 STAT3 written by Po-Chang Shih and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Design of Novel Cancer Therapeutics Through The Validation of PARG as a Therapeutic Target and the Evaluation of Small Molecule Inhibitors of Hypoxia Induced Transcription written by and published by . This book was released on 2010 with total page 470 pages. Available in PDF, EPUB and Kindle. Book excerpt: Because of the severe toxicity and limiting side effects of traditional chemotherapy, there exists a critical need to develop better-tolerated, safer drugs to treat cancer. Recent advances in our understanding of the molecular mechanisms governing carcinogenesis have ushered in a new age in drug discovery and have enabled the design of much more sophisticated agents to treat cancer. This work describes two approaches to the development of novel, specifically targeted cancer therapeutics. The first approach involves the synthesis of a class of a new class of small molecules called epidithiodiketopiperazines (ETPs) designed to inhibit hypoxia-induced transcription. Specifically, these agents block the interaction of the transcription factor HIF-1 & alpha; (hypoxia inducible factor-1 & alpha;) and its required coactivator p300/CBP by inducing a structural change in p300 that renders it incapable of binding to HIF-1 & alpha;. Preventing hypoxia-mediated transcription has the potential to stop the process of angiogenesis that is critical for sustained tumor growth and metastasis. Moreover, because HIF-1 & alpha; also controls genes for energy production and matrix remodeling, ETPs may also halt metabolic adaptation and tumor progression. Our results show that ETPs prevent the association of HIF-1 & alpha; and p300 and abrogate hypoxia signaling on both the transcriptional and translational levels in endogenous systems. In addition, they do not exhibit broad-spectrum cytotoxicity or global inhibition of the transcriptional response. The second approach addresses the validation of poly(ADP-ribose) glycohydrolase (PARG) as a new therapeutic target. This project describes studies aimed to further our understanding of the interaction between poly(ADP-ribose) polymerases (PARPs) and PARG with the ultimate goal of using this knowledge to design novel therapeutics. This portion of the dissertation involves a series of studies in mouse embryonic fibroblasts (MEFs) with genetic mutations in their PARP and PARG function. MEF cell lines containing a truncated form of PARG lacking the regulatory domain demonstrate over-activation of PARP-1, but not PARP-2. Additionally, deletion of the PARG regulatory domain impairs the DNA damage response to SSBs and DSBs and significantly increases cell death resulting from genotoxic stress. Taken together, these studies suggest a specific interaction between PARP-1 and the regulatory domain of PARG that is critical for proper PARP-1 function.

Download or read book Targeting Protein protein Interactions in Transcriptional Complexes as Potential Anti cancer Therapy written by Melanie Amber Blevins and published by . This book was released on 2015 with total page 202 pages. Available in PDF, EPUB and Kindle. Book excerpt: It is widely accepted that the aberrant expression of developmental transcription factors in adult tissues can result in the misexpression of target genes and reactivation of developmental programs, thereby contributing to tumorigenesis and/or tumor progression. I propose that the disruption of the transcriptional activity of developmental transcriptional factors overexpressed in cancer can be an attractive mechanism for potential anti-cancer treatment. The approach through which I hope to disrupt transcription is through the inhibition of the protein-protein interactions between target transcriptional factors and their cofactors. To that end, I have chosen two separate transcriptional complexes each known to be misexpressed and play a causal role in cancer phenotypes: SIX1 and CtBP1. SIX1, a homeobox gene normally expressed during embryogenesis, requires the EYA family of co-activator proteins to activate transcription. CtBP1 is a co-repressor that binds to a conserved peptide motif found in multiple transcription factors (as well as the adenovirus E1A protein) to elicit its effect. Since single amino acid mutations have been shown to significantly disrupt each protein-protein interaction, I hypothesize that only a few residues play an important role in these interactions and that these residue interactions can be disrupted by small molecules leading to decreased protein-protein interactions. To identify small molecule inhibitors that target these complexes, I have developed an AlphaScreen assay to monitor the interaction between SIX1 and EYA2 or CtBP1 and E1A. In collaboration with the National Institute of Health Chemical Genomics Center (NCGC) using a high throughput screen, I have identified compounds that specifically inhibit either the CtBP-E1A or SIX1-EYA2 interactions. These compounds have been validated using secondary, specificity, and cell culture experiments. I plan to further determine the mechanism of action of these compounds through additional biophysical and structural techniques, such as crystallography and isothermal calorimetry. Concurrently, the NCGC is synthesizing a large number of analogues around the lead compounds to improve their potency and solubility, which may facilitate future efforts to characterize their mechanism of action and optimize the compounds. In addition, I am also developing a peptide-based inhibitor of CtBP and its transcription factor partners to inhibit CtBP-mediated tumorigenic and metastatic properties.

Download or read book Small Molecule Inhibitors of Stat3 Protein as Cancer Therapeutic Agents written by Brent Page and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Kinomics written by Heinz-Bernhard Kraatz and published by John Wiley & Sons. This book was released on 2015-11-16 with total page 364 pages. Available in PDF, EPUB and Kindle. Book excerpt: Das umfassende Referenzwerk zur Kinase-Forschung: Ausführlich werden die Themen Kinase-Engineering, Peptidsubstrat-Engineering, das Design von Co-Substraten und Kinasehemmer erläutert sowie deren Anwendung in der Bio- und Pharmaforschung beschrieben.

Download or read book Small molecule Inhibitors of the Transcription Factors STAT5b and STAT5a written by Angela Berg and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: