Project description
New functionalised linkers for targeted proteolysis
Proteolysis targeting chimeras (PROTACs) are small molecules that induce degradation of a target protein, enabling the design of chemical probes and therapeutic agents for previously unreachable proteins. PROTACs are heterobifunctional molecules containing binding ligands to an E3 ubiquitin ligase and a protein of interest, connected by a linker. The formation of a ternary complex of target protein, PROTAC and E3 ligase results in ubiquitination of the target protein followed by degradation in the proteasome. The goal of the EU-funded PREDICT project is to identify and test novel functional linker motifs which will tune up interactions within the ternary complex. The effects of new PROTAC linkers will be systematically studied and used as the basis to design novel functionalised linkers.
Objective
Proteolysis Targeting Chimeras (PROTACs), small molecules capable of inducing degradation of a target protein, represent a novel strategy to design advanced chemical probes and therapeutic agents with the potential to target so far “undruggable” proteins. PROTACs are heterobifunctional molecules consisting of binding ligands to an E3 ubiquitin ligase and a protein of interest, covalently connected by a linker. Formation of a ternary complex of target protein, PROTAC and E3 ligase allows ubiquitination of the target protein, leading to its subsequent degradation by the proteasome. Due to the complexity of this ternary system, rational PROTAC design is highly challenging and novel PROTACs are to date commonly derived from trial-and-error approaches, typically using simple linkers to connect the two binding ligands. The potential to significantly stabilize and in doing so bias productive ternary complex formation, through design of functional linkers has not been exploited so far. My goal for this project is to identify and explore novel functional linker motifs which will enhance interactions within the ternary complex, such as PROTAC-ligase, PROTAC-target as well as cross-interactions between the E3 ligase and the target protein. The effects of halogen bonding, metal coordination and restricted conformational flexibility of the PROTAC linker on ternary complex formation and PROTAC degradation activity and efficiency will be systematically studied, benchmarked against related PROTAC degraders with non-functionalized linkers and taken as the basis to derive valuable structure-activity relationships. My long-term vision is to capitalize on this Fellowship to enhance my career by developing a rational-design strategy for novel PROTAC degraders capitalizing on functionalized linkers to efficiently degrade proteins so far considered to be “undruggable”.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
DD1 4HN Dundee
United Kingdom