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 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 Discovery and Optimization of Novel Small molecular Inhibitors Suppressing Stat3 dependent Tumor Process written by Xiaolei Zhang and published by . This book was released on 2011 with total page 126 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Structure Based Discovery and Testing of Non Peptide Cell Permeable Small Molecule Inhibitors of STAT 3 as a Potential Novel Therapy for Breast Cancer written by and published by . This book was released on 2004 with total page 16 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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.

Download or read book Small Molecule Inhibitors as Anticancer Agents written by Deepak Bhasin and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Signal transducer and activator of transcription 3 (STAT3) is one of the downstream signaling proteins for cytokine and growth factor receptors. Receptor activation induces tyrosine phosphorylation leading to dimerization of two STAT monomers by reciprocal phosphotyrosine-SH2 interactions. This dimer translocates into the nucleus where it controls the transcription of several apoptosis and cell cycle-regulatory proteins. STAT3 has been identified to be overexpressed in many different kinds of blood malignancies and solid tumors. Inhibition of STAT3 dimerization stops translocation into the nucleus and induces apoptosis. Several novel small molecules have been synthesized using a structural-based strategy with an aim to specifically inhibit STAT3 dimerization and have been examined for their antiproliferative activity on breast, pancreatic, prostrate and brain cancer. Among the compounds synthesized, LLL-3, LLL-6 and LLL-12 were found to be active against various cancer cell lines. LLL-12 was found to be the most potent analogue among the LLL series of compounds and even more potent than known inhibitors against various cancer cells overexpressing STAT3, and it did not inhibit STAT1. LLL-12 was also found to reduce tumor growth. Arginine methylation is an important post-translational modification which mainly occurs in nuclear proteins and is involved in structural remodeling of chromatin, signal transduction, cellular proliferation, gene transcription, translation, DNA repair, apoptosis, RNA processing, and mRNA splicing. PRMT5 has been shown to catalyze the formation of monomethylargininie (MMA) and symmetric dimethylarginine (sDMA) on a variety of substrates including myelin basic protein (MBP), the Sm ribonucleoproteins, and additional proteins that require symmetric dimethylarginine residues. PRMT5 has been shown to methylate histones H2A, H3 and H4. PRMT5 has been reported to be associated with tumors. PRMT5 overexpression has been documented in multiple non-Hodgkin's lymphoma cell lines and primary mantle cell lymphoma tumor samples. Molecular docking was used to screen a library of 10,000 compounds to identify 8 potential compounds for biological screening. Subsequent screening identified BLL-1 as our lead compound which was further modified using traditional medicinal chemistry approaches and molecular modeling. BLL-1 was the most potent compound tested on JeKo and Mino cells. Survivin is a 142 amino acid and is the smallest member of the IAP family. Survivin indirectly acts on caspases by associating with cdk4 resulting in release of p21Cip1/Waf1, which interacts with procaspase-3 to suppress Fas mediated cell death. 163 Survivin also provides cytoprotection to cells against caspase-independent cell death by inhibiting the AIF pathway. Survivin is present on the mitotic machinery of dividing cells and regulates cell division. Survivin has been shown to be overexpressed in cancer. Lack of Survivin or disruption of the Survivin function would be expected to cause apoptosis in tumor cells. Structural study of compound 2 showed that its binding site is located at the dimerization interface. Compound 2 was modified with an aim to target the Survivin binding site. LLP-3 was found to be active at 50 um against various cancer cell lines. LLP-3 also delayed mitosis and cells appeared to lose viability after being exposed to LLP-3 for 48 hours.

Download or read book Synthesis of Angucycline based Small Molecules as Potential STAT3 written by Antonio Misale and published by . This book was released on 2012 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Targeting Protein Kinases for Cancer Therapy written by David J. Matthews and published by John Wiley & Sons. This book was released on 2011-09-20 with total page 719 pages. Available in PDF, EPUB and Kindle. Book excerpt: An expert guide to targeting protein kinases in cancer therapy Research has shown that protein kinases can instigate the formation and spread of cancer when they transmit faulty signals inside cells. Because of this fact, pharmaceutical scientists have targeted kinases for intensive study, and have been working to develop medicinal roadblocks to sever their malignant means of communication. Complete with full-color presentations, Targeting Protein Kinases for Cancer Therapy defines the structural features of protein kinases and examines their cellular functions. Combining kinase biology with chemistry and pharmacology applications, this book enlists emerging data to drive the discovery of new cancer-fighting drugs. Valuable information includes: Comprehensive overviews of the major kinase families involved in oncology, integrating protein structure and function, and providing important tools to assist pharmaceutical researchers to understand and work in this dynamic area of cancer drug research Focus on small molecule inhibitors as well as other therapeutic modalities Discussion of kinase inhibitors that have entered clinical trials for the treatment of cancer, with an emphasis on molecules that have progressed to late stage clinical trials and, in a few cases, to market Providing a platform for further study, this important work reviews both the successes and challenges of kinase inhibitor therapy, and provides insight into future directions in the war against cancer.

Download or read book Small Molecule Compounds Targeting DNA Binding Domain of Stat3 for Inhibition of Tumor Growth and Metastasis written by Wei Huang and published by . This book was released on 2014 with total page 390 pages. Available in PDF, EPUB and Kindle. Book excerpt: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors, and its activation is associated with high histological grade and advanced cancer stage. STAT3 has been shown to play important roles in multiple aspects of cancer aggressiveness including proliferation, survival, self-renewal, migration, invasion, angiogenesis and immune response by regulating the expression of diverse downstream target genes. Thus, inhibiting STAT3 promises to be an attractive strategy for treatment of advanced tumors with metastatic potential. We firstly identified a STAT3 inhibitor, inS3-54, by targeting the DNA-binding site of STAT3 using an in-silico screening approach; however, inS3-54 was finally found not to be appropriate for further studies because of low specificity on STAT3 and poor absorption in mice. To develop an effective and specific STAT3 inhibitor, we identified 89 analogues for the structure-activity relationship analysis. By using hematopoietic progenitor cells isolated from wild-type and STAT3 conditional knockout mice, further studies showed that three analogues (A18, A26 and A69) only inhibited STAT3-dependent colony formation of hematopoietic progenitor cells, indicating a higher selectivity for STAT3 than their parental compound, inS3-54. These compounds were found to (1) inhibit STAT3-specific DNA binding activity; (2) bind to STAT3 protein; (3) suppress proliferation of cancer cells harboring aberrant STAT3 signaling; (4) inhibit migration and invasion of cancer cells and (5) inhibit STAT3-dependent expression of downstream targets by blocking the binding of STAT3 to the promoter regions of responsive genes in cells. In addition, A18 can reduce tumor growth in a mouse xenograft model of lung cancer with little effect on body weight. Taken together, we conclude that it is feasible to inhibit STAT3 by targeting its DNA-binding domain for discovery of anticancer therapeutics.

Download or read book Novel STAT3 Small molecule Inhibitors as Potential Anticancer Agents written by Mohammad Rashedul Haque and published by . This book was released on 2011 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Identification of Novel Small Molecule Inhibitors of Proteins Required for Genomic Maintenance and Stability written by Sarah C. Shuck and published by . This book was released on 2010 with total page 262 pages. Available in PDF, EPUB and Kindle. Book excerpt: Targeting uncontrolled cell proliferation and resistance to DNA damaging chemotherapeutics using small molecule inhibitors of proteins involved in these pathways has significant potential in cancer treatment. Several proteins involved in genomic maintenance and stability have been implicated both in the development of cancer and the response to chemotherapeutic treatment. Replication Protein A, RPA, the eukaryotic single-strand DNA binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. Xeroderma Pigmentosum Group A, XPA, is required for nucleotide excision repair, the main pathway cells employ to repair bulky DNA adducts. Both of these proteins have been implicated in tumor progression and chemotherapeutic response. We have identified a novel small molecule that inhibits the in vitro and cellular ssDNA binding activity of RPA, prevents cell cycle progression, induces cytotoxicity and increases the efficacy of chemotherapeutic DNA damaging agents. These results provide new insight into the mechanism of RPA-ssDNA interactions in chromosome maintenance and stability. We have also identified small molecules that prevent the XPA-DNA interaction, which are being investigated for cellular and tumor activity. These results demonstrate the first molecularly targeted eukaryotic DNA binding inhibitors and reveal the utility of targeting a protein-DNA interaction as a therapeutic strategy for cancer treatment.

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 Tumor Oxygenation written by Peter Vaupel and published by Lubrecht & Cramer, Limited. This book was released on 1995 with total page 348 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Molecular Therapies of Cancer written by Georg F. Weber and published by Springer. This book was released on 2015-07-22 with total page 486 pages. Available in PDF, EPUB and Kindle. Book excerpt: Molecular Therapies of Cancer comprehensively covers the molecular mechanisms of anti-cancer drug actions in a comparably systematic fashion. While there is currently available a great deal of literature on anti-cancer drugs, books on the subject are often concoctions of invited review articles superficially connected to one another. There is a lack of comprehensive and systematic text on the topic of molecular therapies in cancer. A further deficit in the relevant literature is a progressive sub-specialization that typically limits textbooks on cancer drugs to cover either pharmacology or medicinal chemistry or signal transduction, rather than explaining molecular drug actions across all those areas; Molecular Therapies of Cancer fills this void. The book is divided into five sections: 1. Molecular Targeting of Cancer Cells; 2. Emerging and Alternative Treatment Modalities; 3. Molecular Targeting of Tumor-Host Interactions; 4. Anti-Cancer Drug Pharmacokinetics; and 5. Supportive Therapies.

Download or read book Multi Drug Resistance in Cancer written by Jun Zhou and published by Humana Press. This book was released on 2012-08-09 with total page 492 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chemotherapy is one of the major treatment options for cancer patients; however, the efficacy of chemotherapeutic management of cancer is severely limited by multidrug resistance, in that cancer cells become simultaneously resistant to many structurally and mechanistically unrelated drugs. In the past three decades, a number of mechanisms by which cancer cells acquire multidrug resistance have been discovered. In addition, the development of agents or strategies to overcome resistance has been the subject of intense study. This book contains comprehensive and up-to-date reviews of multidrug resistance mechanisms, from over-expression of ATP-binding cassette drug transporters such as P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance p- tein to the drug ratio-dependent antagonism and the paradigm of cancer stem cells. The book also includes strategies to overcome multidrug resistance, from the development of compounds that inhibit drug transporter function to the modulation of transporter expression. In addition, this book contains techniques for the detection and imaging of drug transporters, methods for the investigation of drug resistance in animal models, and strategies to evaluate the efficacy of resistance reversal agents. The book intends to provide a state-of-the-art collection of reviews and methods for both basic and clinician investigators who are interested in cancer multidrug resistance mechanisms and reversal strategies. Tianjin, China Jun Zhou v Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1 Multidrug Resistance in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bruce C. Baguley 2 Multidrug Resistance in Oncology and Beyond: From Imaging of Drug Efflux Pumps to Cellular Drug Targets . . . . . . . . . . . . . . . . . . . . . . . . . .

Download or read book The Heterogeneity of Cancer Metabolism written by Anne Le and published by Springer. This book was released on 2018-06-26 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.

Download or read book Principles of Diabetes Mellitus written by Leonid Poretsky and published by Springer Science & Business Media. This book was released on 2002 with total page 788 pages. Available in PDF, EPUB and Kindle. Book excerpt: Diabetes mellitus is a very common disease which affects approximately 150,000,000 worldwide. With its prevalence rising rapidly, diabetes continues to mystify and fascinate both practitioners and investigators by its elusive causes and multitude of This textbook is written for endocrinologists, specialists in other disciplines who treat diabetic patients, primary care physicians, housestaff and medical students. It covers, in a concise and clear manner, all aspects of the disease, from its pathogenesis on the molecular and cellular levels to its most modern therapy.

Download or read book Proteasome Inhibitors in Cancer Therapy written by Julian Adams and published by Springer Science & Business Media. This book was released on 2004-05-25 with total page 319 pages. Available in PDF, EPUB and Kindle. Book excerpt: A panel of leading academic and pharmaceutical investigators takes stock of the remarkable work that has been accomplished to date with proteasome inhibitors in cancer, and examines emerging therapeutic possibilities. The topics range from a discussion of the chemistry and cell biology of the proteasome and the rationale for proteasome inhibitors in cancer to a review of current clinical trials underway. The discussion of rationales for testing proteasome inhibitors in cancer models covers the role of the proteasome in NF-kB activation, the combining of conventional chemotherapy and radiation with proteasome inhibition, notably PS-341, new proteasome methods of inhibiting viral maturation, and the role of protesome inhibition in the treatment of AIDS. The authors also document the development of bortezomib (VelcadeTM) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma.