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DCAF E3 Ligase Exploration To Expand degRadation

Project description

Investigation of DCAF E3 ligase family for expansion of proteolysis targeting chimeras

Proteolysis targeting chimeras (PROTACs) are molecules engineered to induce the degradation of target proteins related to disease. PROTACs contain a ligand that binds an E3 ubiquitin ligase and a ligand for the target protein, which are chemically linked. The complex of ligase, PROTAC and target protein initiates the ubiquitination of the target, followed by proteasomal degradation. Presently, PROTACs utilise about 1 % of known E3 ligases, and the development of PROTACs with different ligases would expand their potential therapeutic application. Funded by the Marie Skłodowska-Curie Actions programme, the DELETER project aims to study structurally, functionally and biophysically the DDB1 and CUL4 associated factors (DCAF) family of E3 ligases as candidates for the PROTACs’ expansion.

Objective

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.

Coordinator

UNIVERSITY OF DUNDEE
Net EU contribution
€ 212 933,76
Address
Nethergate
DD1 4HN Dundee
United Kingdom

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Region
Scotland Eastern Scotland Angus and Dundee City
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 212 933,76