RabTarget4Metastasis · Targeting Rab27A with covalent inhibitors for the treatment of metastatic breast cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-08-01 → 2022-10-29
- EU contribution
- €224,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Targeting Rab27A with covalent inhibitors for the treatment of metastatic breast cancer
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.
Data: CORDIS, © European Union
Project objective
Invasion and metastases remain to date the major causes of cancer mortality around the world. Rab27A is a small GTPase that regulates vesicles trafficking and is involved in many physiological processes, e.g. melanosome transport. Being a small GTPase, Rab27A acts as a molecular switch that cycles between an inactive state (GDP bound) and an active state (GTP bound), in which this protein is able to bind to specific effectors to trigger signalling cascades in cells. Current studies suggest a role for Rab27A in exosome-mediated pre-metastatic niche promotion. Hence, interfering with Rab27A PPIs could be effective in reducing and preventing the occurrence of metastasis in cancer. Small GTPases are renowned as challenging targets and have been long considered undruggable, but the unique presence of two non-conserved cysteines in Rab27A offers a perfect starting point for the development of selective covalent inhibitors. These residues are located in the proximity of a major interaction site with a known effector of Rab27A, Slp2, therefore encouraging for targeting PPIs. A screen of covalent fragments based on the recently developed quantitative Irreversible Tethering (qIT) assay has led to the discovery of novel hits with enhanced reactivity for Rab27A against glutathione. The current project aims to (i) obtain potent Rab27A covalent inhibitors by growing hit fragments, and (ii) demonstrate selective Rab27A target engagement in cells, and efficient disruption of the PPIs of Rab27A with its main effectors. Collaboration with the CRUK Beatson Institute will provide direct access to in vivo models to validate the contribution of Rab27A to metastatic development in cancer by use of such chemical probes, whilst state-of-the-art covalent fragment know-how will be accessed for compound optimisation at the Francis Crick Institute/GSK LinkLab, enabling prompt evaluation of the therapeutic potential of optimised lead compounds that will derive from my work.
Original text from CORDIS.
Participants
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union