Project: Title: Novel Therapies Targeting Epigenetics and Autophagy in Breast and Liver cancer cell lines using Pyrazolopyrimidine Derivatives: Pharmacophore Modelling, Docking, Biological and Toxicological Evaluation
Abstract
Breast and liver cancer cells express various growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF). NFκB is the subject of intense study. NFκB is considered to be a transcription factor controlling expression of many proteins including VEGF and PDGF. Agents capable of suppressing NFκB activation have therapeutic promise and potential to inhibit carcinogenesis. The critical incidence rates of breast and liver carcinoma besides, these crucial biomarkers motivated our research group to design and synthesize novel drug like candidates with potential antitumor activity against breast and liver carcinoma. One of these potential candidates is pyrazolopyrimidine scaffold. Pyrazolo pyrimidines are fused heterocyclic ring systems which known as bio isosteres of adenine, that are necessary for every aspect of cell life. Current treatment strategies for different types of cancer are effective only in a portion of patients. Many factors influence the therapeutic effect, including genetic variations. This study aims to: Design and synthesis of novel pyrazolopyrimidine derivatives with potential antitumor activity. This study will include drug designing, cell culturing and molecular studies techniques to assists and prove our hypothesis. Cell lines culture (HepG2 and MCF-7 cells): to assess and investigate the potential gold role of these pathways targeting as a novel therapeutic strategies. Following drug treatment, cells lysates and nuclear extracts will be subjected to western blotting, qRT-PCR, Western blotting and/or ELISA to determine the different levels of the parameters for investigation of the drugs mechanisms of actions and toxicity studies.
Project Name
Title: Novel Therapies Targeting Epigenetics and Autophagy in Breast and Liver cancer cell lines using Pyrazolopyrimidine Derivatives: Pharmacophore Modelling, Docking, Biological and Toxicological Evaluation
Ref No/ Funded Entity
CRP 2047
Priority
2047
Project Duration
2
Project Start Date
2021-08-25 00:00:00
Project End Date
2023-08-25 00:00:00
Total Budget
350000
Budget of the academy in this project
350000
Objectives
- General Aim: This study aims to: ï€ Design and synthesis of novel pyrazolopyrimidine derivatives with potential antitumor activity. ï€ Determine the influence of these candidates on different types of cancer cells, particularly breast cancer and hepatocellular carcinoma, on which previous and known therapies failed to produce promising and continued effects ï€ Investigation of potential mechanisms of action for these new drugs on various types of cancer. Specific objectives: 1. Design of novel VEGFR inhibitors that may possess potential antitumor activity against breast cancer and hepatocellular carcinoma, through introducing pyrazolopyrimidine ring, bioisosteres of adenine. pyrazolopyrimidine Scaffold along with essential pharmacophoric features may compete with adenosine triphosphate (ATP) for the ATP-binding site of the VEGFR-2 intracellular kinase domain, thereby preventing the intracellular signalling. This leads to inhibition of tumor growth and metastasis. 2. 3D-ligand based pharmacophore model will be constructed to define the essential pharmacophore featured that are crucial to maintain high binding affinity to VEGFR-2. Consequently, novel VEGFR-2 inhibitors hits will be designed. 3. Synthesis of the new designed of pyrazolopyrimidine derivatives through different synthetic pathways. 4. Screening of the new synthesized pyrazolopyrimidine derivatives for other potential targets that may possess potential impact on Breast cancer and liver carcinoma. 5. The tested new medicinal drugs, potential mechanisms of action and their biochemical and molecular pathways and targets will be investigated on both liver and breast carcinoma. 6. The aim also is to minimize cytotoxic doses with the goal of reducing side effects, reducing toxicity and improving therapeutic outcomes. 7. Perform Molecular docking studies on the most active compounds to explain their affinity to the binding site. Furthermore, the molecular modeling job will be enriched with an attempt to validate the stability of the of most active compounds – receptor complex through thermodynamics calculations.
Our Partners
Project Coordinator
yasser
Dean of Scientific Research and Innovation
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E-mail: ygdessouky@yahoo.com
Nour Hammouda
International Programs Coordinator / IT support
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E-mail: nour.sadek@gmail.com
Dr. Albashir Adel Youssef
Assistant Professor
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E-mail: albashir.adel@aast.edu
mohamed youssef omar
Management Department
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