The project entitled “Targeting Rab27A with covalent inhibitors for the treatment of metastatic breast cancer” aimed at investigating a novel approach in the treatment and prevention of breast cancer metastasis. Spreading of the primary tumour to secondary distal sites, i.e. the metastatic process, is the leading cause of cancer death worldwide and unfortunately remains mostly untreatable. Fundamental research such as the one supported by this action is therefore pivotal to help overcome current healthcare barriers and ultimately it will impact patients’ life and enhance treatment options.
This innovative line of research envisioned the validation of a promising therapeutic target, namely the small guanosine triphosphatase (GTPase) protein Rab27A. Recent studies have shown a clear role for Rab27A in supporting the process of tumour migration and invasion. Small GTPases are notoriously challenging targets for small molecule drug discovery. For this reason, we planned to inhibit Rab27A via covalent drugs, which have several advantages and have shown unprecedent potential to address historically challenging targets such as GTPases, as best exemplified by the recently approved Sotorasib, the first clinical inhibitor of a Ras GTPase.
Following promising preliminary results for this work, the following aims were established (as described in detail in the MSCA-IF proposal):
1. Obtaining specific and potent covalent Rab27A inhibitors;
2. Demonstrating engagement of Rab27A in cells and effective inhibition in vitro;
3. Optimising the best compounds for progression towards in vivo models for clinical translatability.
The final report will summarise the main milestones of the project, its current status and further outlook, including tangible output and dissemination activities. In line with project aims, leading a team of 2–4 chemists within the Tate group, we have developed the first chemical probes that engage native Rab27A in cells. Our results will be pivotal to demonstrate the potential of targeting Rab27A as a therapeutic strategy to prevent and combat tumour metastasis. Furthermore, the action has enabled the development of the fellow’s profile for progression into competitive, internationally leading research roles.
