التفاصيل البيبلوغرافية
| العنوان: |
Identifying biologically active small molecules and deciphering their mechanism of action ; Criblage de petites molécules d'intérêt thérapeutique et recherche de leur mécanisme d'action |
| المؤلفون: |
Rozié, Alexandrine |
| المساهمون: |
Toulouse 3, Calsou, Patrick, Britton, Sébastien |
| المصدر: |
Theses.fr |
| سنة النشر: |
2020 |
| مصطلحات موضوعية: |
Réparation de l'ADN, Réponse aux dommages de l'ADN, Points d'arrêt du cycle cellulaire, Petites molécules, Crible phénotypique, Génomique fonctionnelle, Mutagénèse, Petites molécules cliquables, Poison d'ADN topoisomérase, Camptothécine, CHK1, Jaspine B, Céramide, DNA repair, DNA damage response, Cell cycle checkpoints, Small molecules, Phenotypical screen, Functional genomics, Mutagenesis, Clickable small molecules, DNA topoisomerase poison, Camptothecin, envir, psy |
| الوصف: |
The identification of the mechanism of action of small bioactive molecules allows (i) to reveal unexpected pharmacological targets against which new therapeutic molecules that can be developed, (ii) to discover original modes of action that can inspire the development of new drugs, and (iii) to develop biomarkers of response to these treatments. The objective of my thesis was to apply several target identification approaches to small molecules, either new, from a phenotypic screen, or already known but the mechanism of action of which was not identified. In a first part of my work, a phenotypic screen was developed in order to identify in the " Chimiothèque Nationale Essentielle ", new sensitizers to the prototype of a family of DNA-damaging anti-cancer agents, camptothecin (CPT). CPT is a poison of topoisomerase I, inducing a particular type of double-strand DNA breaks (DSB) associated with replication forks. This screen led to the identification of a new sensitizer that we named Shuri1. We have established that Shuri1 induces DSB selectively in replicating cells. We demonstrated that Shuri1 behaves as an inhibitor of the CHK1 protein kinase involved in the signaling of DNA damage. Accordingly, some mutations conferring resistance to a specific CHK1 inhibitor also confer resistance to Shuri1. In a second part of my thesis, I studied the mechanism of action of Jaspine B, a natural molecule derived from marine sponges that exhibits strong cytotoxicity against different human solid tumor cell lines. Previously, several mechanisms have been proposed for Jaspine B, but none accounts for the cellular effects of this molecule. In collaboration with Yves Génisson's team at the SPCMIB in Toulouse, a clickable analogue of jaspine B was synthesized and was localized by cell microscopy as aggregates at the endoplasmic reticulum (ER). Using lipidomics, functional genomics and real-time imaging, we have established a model of the Jaspine B mechanism of action in cancer cells. My work supports that Jaspine B behaves as a ... |
| نوع الوثيقة: |
thesis |
| اللغة: |
French |
| العلاقة: |
10670/1.aimhpr; http://www.theses.fr/2020TOU30246Test |
| الإتاحة: |
http://www.theses.fr/2020TOU30246Test |
| حقوق: |
other |
| رقم الانضمام: |
edsbas.56AFB54F |
| قاعدة البيانات: |
BASE |
