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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.

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

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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