PREDICT · PROTAC Linker Design: towards Functionality
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-07-01 → 2023-06-30
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
PROTAC Linker Design: towards Functionality
Proteolysis targeting chimeras (PROTACs) are small molecules that are designed to induce degradation of a target protein and represent a new strategy to design chemical probes and therapeutic agents of previously “undruggable” proteins. PROTACs are bifunctional molecules consisting of binding ligands to a target protein and an E3 ligase, a protein used in a cell’s tagging process of proteins with ubiquitin for recognition by the cell’s own degradation mechanism, connected by a linker. PROTACs are developed to enable the formation of a ternary complex of target protein, PROTAC and E3 ligase that results in tagging of the non-natural target protein with ubiquitin and subsequent degradation using cellular mechanisms. Commonly, the linker portion of a PROTAC is considered to be a “spacer” of appropriate length between both ligands enabling ternary complex formation. Linkers of PROTACs are mostly optimized with regard to their length, lipophilicity and privileged conformation, e.g. being already preorganised for binding to target and E3 ligase. The goal of this project is to design, develop and assess the utility a novel linker motif that adds a new function to the linker. This function was leveraged to develop a novel hit-identification assay that is envisioned to accelerate development of degrader candidates in PROTAC drug discovery projects.
Data: CORDIS, © European Union
Project 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”.
Original text from CORDIS.
Participants
- UNIVERSITY OF DUNDEE · DundeeCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union