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RabTarget4Metastasis SIGNED

Targeting Rab27A with covalent inhibitors for the treatment of metastatic breast cancer

Total Cost €

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EC-Contrib. €

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Partnership

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 RabTarget4Metastasis project word cloud

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derive    metastases    mediated    inactive    probes    offers    disruption    signalling    ppis    prompt    covalent    occurrence    therapeutic    cascades    assay    vivo    inhibitors    accessed    irreversible    screen    compounds    obtain    compound    validate    fragment    molecular    cancer    metastatic    chemical    cycles    undruggable    selective    effector    perfect    date    encouraging    reducing    gtpase    protein    interfering    conserved    gdp    cells    engagement    site    suggest    invasion    world    preventing    linklab    contribution    effectors    rab27a    gtp    mortality    hence    located    tethering    gtpases    starting    trafficking    physiological    causes    slp2    trigger    whilst    fragments    quantitative    bound    proximity    cruk    switch    qit    models    metastasis    niche    discovery    hit    optimisation    regulates    acts    bind    transport    reactivity    beatson    exosome    vesicles    small    point    cysteines    efficient    promotion    evaluation    francis    gsk    interaction    hits    crick    glutathione    renowned    residues    active    melanosome    direct    led    enhanced    potent   

Project "RabTarget4Metastasis" data sheet

The following table provides information about the project.

Coordinator
IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE 

Organization address
address: SOUTH KENSINGTON CAMPUS EXHIBITION ROAD
city: LONDON
postcode: SW7 2AZ
website: http://www.imperial.ac.uk/

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Total cost 224˙933 €
 EC max contribution 224˙933 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2019
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2020
 Duration (year-month-day) from 2020-08-01   to  2022-07-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE UK (LONDON) coordinator 224˙933.00

Map

 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.

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