| Titre : | THE ANTI-PROLIFERATIVE THERAPEUTIC POTENTIAL OF A SERIES OF PYRAZOLES DERIVATIVES VIA A COMPUTATIONAL STUDY AND IDENTIFICATION OF SMALL MOLECULES INHIBITING THE PROLIFERATION OF B16-F10, ACTIVATING T CELLS AND TARGETING RAF1, C-KIT | | Type de document : | thèse | | Auteurs : | BENNANI FATIMA EZZAHRA, Auteur | | Année de publication : | 2022/2023 | | Langues : | Anglais (eng) | | Mots-clés : | Anticancer drug discovery Bioinformatics Chemoinformatics Pyrazole
derivatives 2D_QSAR Quantitative structure-activity relationship Molecular Dynamics
simulations ADME_T Cancer cell lines Targeted therapy EGFR RSK1 Découverte de médicaments anticancéreux Bioinformatique Chémoinformatique Dérivés de pyrazole Relation quantitatif-structure-activité en 2D (2D_QSAR) Simulations de
dynamique moléculaire ADME_T Lignées cellulaires cancéreuses Thérapie ciblée, EGFR,
RSK1 RAF1 PARP2 LIN28B CRMP2 C-RAF CYP17 c-KIT+ VEGFR HDAC9 PD1 IFNG GZMB, Raf_1 Thérapie du mélanome Inhibition des points de contrôle immunitaires RAF1 PARP2 اكتشاف دواء مضاد للسرطان، علوم المعلومات الحيوية، علوم الكيمونفورماتيكس، مشتقات البيرازول عالقة الهيكل النشطية الكمية2 D_QSAR محاكاة الديناميات الجزيئية ADME_T خطوط خاليا السرطان العالج EGFR SK1 RAF1 ،PARP2 LIN28B ،CRMP2 C-RAF CYP17 c-KIT+
VEGFR HDAC9 PD1 IFNG GZMB Raf_1عالج ميالنوما، عائقات نظام المناع
LIN28B, CRMP2, C-RAF, CYP17, c-KIT+ VEGFR, HDAC9, PD1, IFNG, GZMB, Raf_1,
melanoma therapy, Immune checkpoint blockade | | Résumé : | Cancer remains a global leading cause of death, posing an ongoing challenge despite
substantial progress in anticancer drug discovery. The integration of bioinformatics and
chemoinformatics has reshaped this field, streamlined processes, and reduced both time and
costs compared to traditional methods. This study employs computational techniques to
evaluate 63 synthesized pyrazole derivatives against 12 cancer cell lines, employing 2D
quantitative structure-activity relationship analysis (2D_QSAR). Molecular and dynamics
simulations target 11 prominent cancer therap.In this thesis,we predict the anticancer
potential, measured as pIC50 values, of pyrazole derivatives synthesized in-house across 12
distinct cancer cell lines. We utilize two statistical approaches, Principal Component Analysis
(PCA) and Partial Least Squares (PLS), yielding 12 2D-QSAR models. Notably, the pyrazole
demonstrates considerable antiproliferative efficacy, with pIC50 values of A-549 Lung
cancer (pIC50=9.13), MCF-7 Breast cancer (6.53<pIC50<6.88), Hela Cervical cancer
(7.19<pIC50<7.27), HepG-2 Liver cancer (5.80<pIC50<5.83), PaCa2 Pancreatic cancer
(5.89<pIC50<6.22), DLD-1 Colon cancer (7.88<pIC50<8.32), PC-3 Prostate cancer
(5.14<pCI50<5), B16-F10 Melanoma (6.30<pIC50<6.73), K562 Leukemia (pIC50=7.31),
MDA-MB-231 Breast cancer (5.89<pIC50<7.03), A2780 Ovarian cancer (8.15<pIC50<8.63),
and ACHN Kidney cancer (5.87<pCI50<6.48).Additionally, through molecular docking and
dynamics simulation studies, we identify potent pyrazole-based inhibitors/modulators against
EGFR, RSK1, RAF1, PARP2, LIN28B, CRMP2, C-RAF, CYP17, c-KIT+ VEGFR, and
HDAC9. The analyses suggest that the compounds, M33, M36, M72, M74, M76, and M77,
hold promise as inhibitors or modulators targeting these objectives. Finally, in vitro and in
vivo experiments highlight M15 as a promising candidate it effectively inhibits B16-F10 cell
proliferation with an IC50 of 3.31 μg/ml while concurrently activating T-cells expressing
various biomarkers, including CD4, CD8, Ki67, PD1, IFNG, and GZMB. Furthermore, it
modulates the expression of Raf_1 and C-Kit. Remarkably, in vivo assays confirm that M15
suppresses tumor growth, enhances effector cells, and diminishes exhausted cells. | | Numéro (Thèse ou Mémoire) : | D0162022 | | Président : | Yahia CHERRAH | | Directeur : | Moulay Elabbes FAOUZI ; Christopher E. RUDD ; | | Juge : | M’hammed ANSAR | | Juge : | El Mostafa EL FAHIME ; Mourad ER-RASFA ; Youssef RAMLI ; | | Juge : | Hicham BELLAOUI ; Saïd EL KAZZOULI ; Brahim LAKHAL Invité d’ |
THE ANTI-PROLIFERATIVE THERAPEUTIC POTENTIAL OF A SERIES OF PYRAZOLES DERIVATIVES VIA A COMPUTATIONAL STUDY AND IDENTIFICATION OF SMALL MOLECULES INHIBITING THE PROLIFERATION OF B16-F10, ACTIVATING T CELLS AND TARGETING RAF1, C-KIT [thèse] / BENNANI FATIMA EZZAHRA, Auteur . - 2022/2023. Langues : Anglais ( eng) | Mots-clés : | Anticancer drug discovery Bioinformatics Chemoinformatics Pyrazole
derivatives 2D_QSAR Quantitative structure-activity relationship Molecular Dynamics
simulations ADME_T Cancer cell lines Targeted therapy EGFR RSK1 Découverte de médicaments anticancéreux Bioinformatique Chémoinformatique Dérivés de pyrazole Relation quantitatif-structure-activité en 2D (2D_QSAR) Simulations de
dynamique moléculaire ADME_T Lignées cellulaires cancéreuses Thérapie ciblée, EGFR,
RSK1 RAF1 PARP2 LIN28B CRMP2 C-RAF CYP17 c-KIT+ VEGFR HDAC9 PD1 IFNG GZMB, Raf_1 Thérapie du mélanome Inhibition des points de contrôle immunitaires RAF1 PARP2 اكتشاف دواء مضاد للسرطان، علوم المعلومات الحيوية، علوم الكيمونفورماتيكس، مشتقات البيرازول عالقة الهيكل النشطية الكمية2 D_QSAR محاكاة الديناميات الجزيئية ADME_T خطوط خاليا السرطان العالج EGFR SK1 RAF1 ،PARP2 LIN28B ،CRMP2 C-RAF CYP17 c-KIT+
VEGFR HDAC9 PD1 IFNG GZMB Raf_1عالج ميالنوما، عائقات نظام المناع
LIN28B, CRMP2, C-RAF, CYP17, c-KIT+ VEGFR, HDAC9, PD1, IFNG, GZMB, Raf_1,
melanoma therapy, Immune checkpoint blockade | | Résumé : | Cancer remains a global leading cause of death, posing an ongoing challenge despite
substantial progress in anticancer drug discovery. The integration of bioinformatics and
chemoinformatics has reshaped this field, streamlined processes, and reduced both time and
costs compared to traditional methods. This study employs computational techniques to
evaluate 63 synthesized pyrazole derivatives against 12 cancer cell lines, employing 2D
quantitative structure-activity relationship analysis (2D_QSAR). Molecular and dynamics
simulations target 11 prominent cancer therap.In this thesis,we predict the anticancer
potential, measured as pIC50 values, of pyrazole derivatives synthesized in-house across 12
distinct cancer cell lines. We utilize two statistical approaches, Principal Component Analysis
(PCA) and Partial Least Squares (PLS), yielding 12 2D-QSAR models. Notably, the pyrazole
demonstrates considerable antiproliferative efficacy, with pIC50 values of A-549 Lung
cancer (pIC50=9.13), MCF-7 Breast cancer (6.53<pIC50<6.88), Hela Cervical cancer
(7.19<pIC50<7.27), HepG-2 Liver cancer (5.80<pIC50<5.83), PaCa2 Pancreatic cancer
(5.89<pIC50<6.22), DLD-1 Colon cancer (7.88<pIC50<8.32), PC-3 Prostate cancer
(5.14<pCI50<5), B16-F10 Melanoma (6.30<pIC50<6.73), K562 Leukemia (pIC50=7.31),
MDA-MB-231 Breast cancer (5.89<pIC50<7.03), A2780 Ovarian cancer (8.15<pIC50<8.63),
and ACHN Kidney cancer (5.87<pCI50<6.48).Additionally, through molecular docking and
dynamics simulation studies, we identify potent pyrazole-based inhibitors/modulators against
EGFR, RSK1, RAF1, PARP2, LIN28B, CRMP2, C-RAF, CYP17, c-KIT+ VEGFR, and
HDAC9. The analyses suggest that the compounds, M33, M36, M72, M74, M76, and M77,
hold promise as inhibitors or modulators targeting these objectives. Finally, in vitro and in
vivo experiments highlight M15 as a promising candidate it effectively inhibits B16-F10 cell
proliferation with an IC50 of 3.31 μg/ml while concurrently activating T-cells expressing
various biomarkers, including CD4, CD8, Ki67, PD1, IFNG, and GZMB. Furthermore, it
modulates the expression of Raf_1 and C-Kit. Remarkably, in vivo assays confirm that M15
suppresses tumor growth, enhances effector cells, and diminishes exhausted cells. | | Numéro (Thèse ou Mémoire) : | D0162022 | | Président : | Yahia CHERRAH | | Directeur : | Moulay Elabbes FAOUZI ; Christopher E. RUDD ; | | Juge : | M’hammed ANSAR | | Juge : | El Mostafa EL FAHIME ; Mourad ER-RASFA ; Youssef RAMLI ; | | Juge : | Hicham BELLAOUI ; Saïd EL KAZZOULI ; Brahim LAKHAL Invité d’ |
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