Developing Small Molecule Inhibitors for P21 to Pave the Way for Novel Therapeutic Approaches for Breast Cancer and Other Cancers PDF Download
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Author: Tanya A. Zeigler
Publisher:
ISBN:
Category :
Languages : en
Pages : 144
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Book Description
Author: Tanya A. Zeigler
Publisher:
ISBN:
Category :
Languages : en
Pages : 144
Get Book Here
Book Description
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
Transforming Growth Factor-Betas (TGF beta) are polypeptides that are constitutively secreted and activated by many breast carcinomas. They contribute to the tumor's ability to invade and metastasize, to induce angiogenesis and to escape from immune destruction. These circumstances raise the question whether blocking the effects of tumor-derived TGF beta on normal tissue (stroma, bloodvessels and immune cells) could be developed as a novel approach to the treatment of breast cancer. We propose to block TGF beta action by developing small molecules that inhibit the type I TGF beta receptor kinase, which is the key molecule that initiates and mediates TGF beta signaling. We plan to develop a cell free ELISA-type as say for high-throughput screening for selective inhibitors of T beta R-I kinase activity by using an antibody that specifically detects the phosphorylated form of its substrate, Smad2. Combinatorial libraries of small molecules will then be screened for potent and highly selective for the T beta R-I kinase. These will then be tested against normal cells in vitro using a number of different assays for TGF beta's biological effects. Promising compounds will then be tested for their antitumor activity against highly metastatic, - angiogenic and immunogenic varieties of transplantable breast cancers in mice.
Author: Nicole A. Wilson
Publisher:
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Category :
Languages : en
Pages : 0
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Metastatic disease is the major cause of morbidity and mortality in women with breast cancer. DLC1 codes for a Rho-GTPase activating protein that has both tumour and metastasis suppressor functions. Diminished DLC1 expression occurs in ~50% of breast cancers, thereby making it an ideal candidate for therapeutic interventions that could conceivably target both primary and metastatic disease. In this thesis, I employed a CRISPR-Cas9 gene editing approach to generate syngeneic heterozygous and homozygous DLC1-deleted breast cell lines. Using these cell lines and non-target controls, synthetic lethal (SL) assays were performed to identify candidate genes that could be used as drug targets to selectively kill the DLC1-deleted cell lines. To generate DLC1-deleted breast cell models, I employed CRISPR-Cas9 gene editing in malignant MCF7 and immortalized 184-hTERT breast cell lines. In a population of edited MCF7 cells, I achieved 40-60% reduction in DLC1 protein expression as determined by Western blot analysis. In 184-hTERT cells, clonal heterozygous (DLC1-HET) and homozygous DLC1 deleted (DLC1-KO) cell lines were generated and confirmed via DNA sequencing and Western blot analyses. Candidate drug targets were assessed in the 184-hTERT clonal cell lines for SL interactions with DLC1 deletion. I directly assessed MYH9, DNMT1 and the four members of the FBXW7-SCF complex, using siRNA-based SL assays. MYH9 inhibition resulted in a small but statistically significant decrease in cell numbers between the non-target (NT) control cell line and DLC1-HET. Blebbistatin, a small-molecule inhibitor of the MYH9-containing complex non-muscle myosin II, was assessed as a potential therapeutic agent. Dose-response curves were generated, and the EC50 was compared between cell lines. Blebbistatin treatment resulted in a small decrease in EC50 values in the DLC1-HET compared to NT. In this thesis, DLC1 deleted cellular models were generated and validated. Six preliminary candidate drug targets were assessed in the generated cell lines through SL assays. Further assessment of candidate therapeutic targets using these DLC1-deleted cellular models may result in the identification of novel therapeutic targets of DLC1-deficient tumours that may minimize the morbidity and mortality associated with primary and metastatic disease in breast cancer patients.
Author: John Lazo
Publisher:
ISBN:
Category :
Languages : en
Pages : 117
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Book Description
Our overall goal of this US Army Breast Cancer Grant entitled "Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases" is to identify and develop novel therapeutic agents for human breast cancer. During the past year we synthesized a novel second generation, small molecule library designed on our previous natural product pharmacophore that was targeted against oncogenes implicated in human breast cancer, namely the dual specificity phosphatases (DSP) Cdc25. The new library maintains unique, rigid backbone structures that should provide more structural information about the active site of DSP. Several of the new compounds are potent competitive inhibitors of Cdc25. In addition we have identified the first selective VHR inhibitor, namely FY2-alpha009. This compound should facilitate our studies of the biological function of VHR, which are currently unknown. We continued our studies of the prototype member of the first combinatorial library with the best antiCdc25 activity, namely SC-alpha alpha delta89. We have determined that SC-alpha alpha 89 is selectively cytotoxic to cells, which overexpress Cdc25B due to transformation with SV-40 large T antigen. We have also discovered that SC-alpha alpha 89 disrupts a key mitogenic and antiapoptotic pathway, insulin-like growth factor-1 (lGF-1), and downregulates Cdc2 expression. SC--alpha alpha89 also blocks human breast cancer (MDA-MB-231) and other cells at G2IM consistent with Cdc25B or C inhibition. Thus, our combinatorial approach for selective DSP inhibitors remains very promising.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 8
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Transforming Growth Factor-Bs (TGFBeta)are polypeptides that are constitutively secreted and activated by many breast carcinomas. They contribute to the tumor's ability to invade and metastasize, to induce angiogenesis and to escape from immune destruction. These circumstances raise the question whether blocking the effects of tumor-derived TGFBeta on normal tissue (stroma, bloodvessels and immune cells) could be developed as a novel approach to the treatment of breast cancer. We propose to block TGFBeta action by developing small molecules that inhibit the type I TGFBeta receptor kinase, which is the key molecule that initiates and mediates TGFBeta signaling. We plan to develop a cell free ELISA-type assay for high-throughput screening for selective inhibitors of TBR-I kinase activity by using an antibody that specifically detects the phosphorylated form of its substrate, Smad2. Combinatorial libraries of small molecules will then be screened for potent and highly selective for the TBR-I kinase. These will then be tested against normal cells in vitro using a number of different assays for TGFBeta's biological effects. Promising compounds will then be tested for their antitumor activity against highly metastatic, - angiogenic and immunogenic varieties of transplantable breast cancers in mice.
Author: Mengwu Pan
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 16
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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.
Author: Nicola J. Curtin
Publisher: Humana Press
ISBN: 3319141511
Category : Medical
Languages : en
Pages : 590
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Book Description
PARP Inhibitors for Cancer Therapy provides a comprehensive overview of the role of PARP in cancer therapy. The volume covers the history of the discovery of PARP (poly ADP ribose polymerase) and its role in DNA repair. In addition, a description of discovery of the PARP family, and other DNA maintenance-associated PARPs will also be discussed. The volume also features a section on accessible chemistry behind the development of inhibitors. PARP inhibitors are a group of pharmacological inhibitors that are a particularly good target for cancer therapy. PARP plays a pivotal role in DNA repair and may contribute to the therapeutic resistance to DNA damaging agents used to treat cancer. Researchers have learned a tremendous amount about the biology of PARP and how tumour-specific defects in DNA repair can be exploited by PARPi. The “synthetic lethality” of PARPi is an exciting concept for cancer therapy and has led to a heightened activity in this area.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 9
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Book Description
Transforming Growth Factor-beta (TGF-beta) are polypeptides that are constitutively secreted and activated by many breast carcinomas. They contribute to the tumor's ability to invade and metastasize, to induce angiogenesis and to escape from immune destruction. These circumstances raise the question whether blocking the effects of tumor-derived TGF-beta on normal tissue (stroma, blood vessels and immune cells) could be developed as a novel approach to the treatment of breast cancer. We propose to block TGF-beta action by developing small molecules that inhibit the type I TGF-beta receptor kinase, which is the key molecule that initiates and mediates TGF-beta signaling. We plan to develop a cell free ELISA-type assay for high-throughput screening for selective inhibitors of T beta R-I kinase activity by using an antibody that specifically detects the phosphorylated form of its substrate, Smad2. Combinatorial libraries of small molecules will then be screened for potent and highly selective for the T beta R-I kinase. These will then be tested against normal cells in vitro using a number of different assays for TGF-beta's biological effects. Promising compounds will then be tested for their antitumor activity against highly metastatic, - anqioqenic and immunoqenic varieties of transplantable breast cancers in mice.
Author: Monica Mita
Publisher: Springer
ISBN: 9782817804910
Category : Medical
Languages : en
Pages : 0
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Book Description
This book describes the challenges involved in developing mTOR inhibitors for cancer treatment, starting with an in-depth examination of their molecular mechanism of action, with emphasis on the class side-effects, efficacy and mechanisms of resistance, as well as on promising novel directions for their development, including novel compounds and rational combinations with other anti-neoplastic drugs. Over the last 10 years, inhibitors of mTOR have emerged as a major class of anticancer drugs. Two rapamycin analogs are currently approved for the treatment of renal cell carcinoma, and it is estimated that a variety of other tumor types could benefit from mTOR inhibition, with numerous clinical trials (including pivotal registration trials) already underway. Second-generation small-molecule inhibitors of the pathway have also shown promise in terms of their superior tolerability and efficacy and are undergoing extensive clinical evaluation, with an estimated 30+ compounds currently under evaluation.
