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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

Explore the words cloud of the RabTarget4Metastasis project. It provides you a very rough idea of what is the project "RabTarget4Metastasis" about.

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

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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