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CORDIS

DCAF E3 Ligase Exploration To Expand degRadation

Projektbeschreibung

Untersuchung der DCAF E3-Ligasenfamilie zur Erweiterung der PROTACs-Substanzklasse

„Proteolysis Targeting Chimeras“ (PROTACs) sind Moleküle, die derart konstruiert sind, dass sie den Abbau von mit Krankheiten assoziierten Zielproteinen auslösen. PROTACs enthalten einen Liganden, der eine E3-Ubiquitin-Ligase bindet, sowie einen Liganden für das Zielprotein, die chemisch miteinander verbunden sind. Der Komplex aus Ligase, PROTAC und Zielprotein leitet die Ubiquitinierung des Zielproteins ein. Es folgt der Abbau im Proteasom der Zelle. Gegenwärtig kommt bei den PROTACs etwa 1 % der bekannten E3-Ligasen zum Einsatz. Die Entwicklung von PROTACs mit anderen Ligasen würde ihren potenziellen therapeutischen Anwendungsbereich erweitern. Ziel des im Rahmen der Marie-Skłodowska-Curie-Maßnahmen finanzierten Projekts DELETER ist die strukturelle, funktionelle und biophysikalische Erforschung von E3-Ligasen einschließlich der DDB1- und CUL4-assoziierten Faktoren (DCAF) als potenzielle Kandidaten für die Erweiterung der PROTACs-Substanzklasse.

Ziel

PROteolysis TArgeting Chimeras (PROTACs) are molecules with therapeutic potential that induce degradation of target proteins involved in disease. PROTACs are composed of a ligand that binds an E3 ubiquitin ligase, chemically linked to a ligand for the target protein. Formation of a ternary complex between ligase, PROTAC and target protein leads to ubiquitination of the target, which is then recognised by the proteasome and degraded. The vast majority of PROTAC degraders developed to date recruit either the VHL or Cereblon E3 ligases, and only ~1% of the >600 known E3 ligases have been harnessed by this type of molecule. However, a given E3 ligase may not always form ternary complexes productive to ubiquitination for every target, and considerations such as organelle, cell type and tissue specificity warrant exploration of E3 ligases beyond those for which ligands currently exist. In this Fellowship, I will pursue the DCAF family of E3 ligases to expand the PROTAC toolbox. Two DCAF proteins have been successfully hijacked by degraders such as PROTACs, validating the family as exploitable for targeted protein degradation, and most DCAF proteins contain a WD40 repeat domain that is ligandable i.e. tractable to small molecule binding. Certain DCAF proteins also display organelle and tissue specificity. Beyond their potential for PROTAC development, DCAF proteins are therapeutically relevant in their own right and have been implicated in diseases such as cancer. DELETER will explore this high-potential yet understudied family of E3 ligases structurally, functionally and biophysically. High-quality recombinant proteins and relevant reagents produced in this project will be used to engage in screening campaigns to identify ligands that will be developed into PROTACs and inhibitors. The information, reagents and compounds generated for DCAFs will expand the scope of targeted protein degradation and has potential to increase the number of targets degradable by PROTACs.

Koordinator

UNIVERSITY OF DUNDEE
Netto-EU-Beitrag
€ 212 933,76
Adresse
Nethergate
DD1 4HN Dundee
Vereinigtes Königreich

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Region
Scotland Eastern Scotland Angus and Dundee City
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 212 933,76