Projektbeschreibung
PI3K-Signalaktivierung als Strategie zur Krebsbekämpfung
Die Signalübertragung durch Phosphoinositid-3-Kinase (PI3K) ist für viele biologische Funktionen von zentraler Bedeutung und weist bei Krebs eine aberrante Regulierung auf. Das EU-finanzierte Projekt PI3K MODULATORS zielt auf die Hyperaktivierung des PI3K-Signalwegs in weißen Blutkörperchen als therapeutische Intervention bei hämatologischen Malignomen. Zu diesem Zweck werden die Forschenden einen Ansatz für ein Hochdurchsatz-Screening durchführen, um niedermolekulare PI3K-Aktivatoren zu identifizieren, die spezifisch für die weiße Blutkörperchen-Isoform von PI3K sind. Sie werden die Wirkungsweise dieser Aktivatoren sowie den Mechanismus des PI3K-vermittelten Krebszellentodes durch verschiedene strukturelle und biochemische Analysen untersuchen. Die Ergebnisse des Projekts werden den Weg für den Einsatz von PI3K-Medikamenten in der Krebstherapie ebnen.
Ziel
PI3K signalling is a critical regulator of many cellular functions including cell growth and survival, and is deregulated in cancer and auto-immunity.
This proposal is based on the concept to cause cell death by hyperactivating signalling in cancer cells above a tolerable threshold. This idea has been previously proposed for other kinases, but no small-molecule activators were available to formally test the idea.
This proposal focuses on activators of the leukocyte-enriched PI3Kd, an isoform of PI3K that is involved in immune regulation and haematological malignancies.
The 3 key objectives and their approaches are:
1. To discover and characterise small-molecule PI3Kd activators. This will be achieved using a combination of virtual screening and high throughput screening.
2. To understand the mechanism of PI3Kd activation. This enables understanding of how these activators function, and provides structural data that can be used for structure-based design and compound improvement. This will be achieved using structural biology (HDX-MS and crystallography), biochemical (lipid kinase) and biophysical (binding) assays.
3. To determine the activity of PI3Kd activators in haematopoietic malignancies. In order to use PI3Kd activators in cancer therapy, it is critical to determine the conditions under which hyperactivation of PI3Kd results in cancer cell death. This will be achieved with a panel of B and T-cell lymphoma cell lines using cell viability assays under different conditions.
These objectives integrate my expertise in compound screening, molecular modelling and compound design with the world-leading expertise of the Host Lab in PI3K signalling, cancer biology and drug development. This proposal aims to make breakthroughs in understanding PI3K signalling, its exploitation in drug development and in cancer-therapy. This will be a key turning point in my scientific career and facilitate PI3K drug development collaborations of the Host Lab with the pharmaceutica.
Wissenschaftliches Gebiet
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural sciencesearth and related environmental sciencesgeologymineralogycrystallography
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesmolecular biologystructural biology
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
MSCA-IF-EF-ST - Standard EFKoordinator
WC1E 6BT London
Vereinigtes Königreich