Timothy LANGLAIS PhD defense

Development of a novel blood brain barrier permable IRE1 inhibitors for adjuvant therapy in glioblastoma
Timothy LANGLAIS PhD defense

Thuesday December 13, 2022 - 9:00

Beaulieu Campus, Rennes
Building 2A, Louis-Antoine Amphitheater


Organic Chemistry & Interfaces team

 

Abstract

Glioblastoma multiform is one of the most aggressive primary brain cancers and the current treatment, based on Stupp protocol, marginally improves survival (15 months) with near-systematic relapse.

Recently, studies have shown the possibility to resensitize cancer cells to chemotherapy using small molecules active on IRE1, a transmembrane protein of the endoplasmic reticulum. This protein is activated under proteic stress, intrinsic conditions of cancer cells, and allows the cell to adapt to the various physiological modifications it may undergo, including pharmacological treatments. Recently, research conducted by the PROSAC team has led to the discovery of a small molecule named Z4P. This blood-brain-barrier permeable compound can inhibits IRE1 and its associated activities in order to resensitize glioblastoma cells to chemotherapy. When Z4P is used in combinaison with Temozolomide, a chemotherapy agent, we observe in murine models xenografted with human GB a significant decrease in tumor size, without relapse.

This manuscript relates the work carried out on the Structure-Activity Relationships study of Z4P in order to better understand its binding mode and to improve its drug-likeness.

Jury

  • Patricia Melnyk, Professeure, Université de Lille, UFR3S / Rapportrice
  • Florence Mahuteau-Betzer, Directrice de recherche, Institut Curie, UMR9187 / U1196 / Rapportrice
  • Sophie Tomasi, Professeure, Université de Rennes 1, France / Présidente/Examinatrice
  • François Hallé, Maitre de conférences, Université de Lyon, France / Examinateur
  • François Carreaux, Maitre de conférences, Université de Rennes 1, France / Directeur de thèse
  • Nicolas Gouault, Maitre de conférences, Université de Rennes 1, France / Co-Directeur de thèse
  • Éric Chevet,  Directeur de recherche, INSERM U1242, Rennes, France / Invité
  • Xavier Guillory, Chercheur, Université de Rennes 1, Rennes, France / Invité

Contacts

  • François Carreaux, francois [dot] carreauxatuniv-rennes1 [dot] fr
  • Nicolas Gouault, nicolas [dot] gouaultatuniv-rennes1 [dot] fr