A new Met inhibitory-scaffold identified by a focused forward chemical biological screen.

Salvatore Patané; Nicolas Pietrancosta; Hessameh Hassani; Vincent Leroux; Bernard Maigret; Jean-Louis Kraus; Rosanna Dono; Flavio Maina

inria-00339127, version 1

A new Met inhibitory-scaffold identified by a focused forward chemical biological screen.

Salvatore Patané ¹, Nicolas Pietrancosta ¹, Hessameh Hassani ¹, Vincent Leroux ², Bernard Maigret ², Jean-Louis Kraus, Rosanna Dono ¹, Flavio Maina ¹

Biochemical and Biophysical Research Communications / Biochemistry and Biophysics Research Communications 375, 2 (2008) 184-189

1: Institut de Biologie du Développement de Marseille Luminy (IBDML)
http://www.ibdml.univ-mrs.fr
CNRS : UMR6216 – Université de la Méditerranée - Aix-Marseille II Case 907 - Parc Scientifique de Luminy 13288 Marseille Cedex 9 France
2: ORPAILLEUR (INRIA Lorraine - LORIA)
INRIA – CNRS : UMR7503 – Université Henri Poincaré - Nancy I – Université Nancy II – Institut National Polytechnique de Lorraine (INPL) France

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inria-00339127, version 1
http://hal.inria.fr/inria-00339127
oai:hal.inria.fr:inria-00339127
From: Malika Smail-Tabbone <>
Submitted on: Sunday, 16 November 2008 23:13:17
Updated on: Monday, 17 November 2008 11:36:20

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%% inria-00339127, version 1
%% http://hal.inria.fr/inria-00339127
@article{patane:inria-00339127,
    hal_id = {inria-00339127},
    url = {http://hal.inria.fr/inria-00339127},
    title = {{A new Met inhibitory-scaffold identified by a focused forward chemical biological screen.}},
    author = {Patan{\'e}, Salvatore and Pietrancosta, Nicolas and Hassani, Hessameh and Leroux, Vincent and Maigret, Bernard and Kraus, Jean-Louis and Dono, Rosanna and Maina, Flavio},
    abstract = {{The receptor tyrosine kinase Met is crucial for the genetic program causing cancer progression and metastasis. Its nodal function during aggressiveness and resistance acquisition poses Met inhibition as an obligatory step in anti-cancer targeted therapy. Here, we applied a "Met-focussed" forward chemical biological screen to discover new agents antagonizing Met-triggered biological functions. The identified new scaffold, JLK1360, has a dual mechanism of action towards Met: it impairs Met signalling and also prevents its restoration after degradation. Docking and molecular dynamics provide evidences on the interacting mode of JLK1360 within the Met ATP-binding pocket. Moreover, computational and biochemical studies also highlighted that JLK1360 has a good degree of selectivity towards Met than other RTKs tested. Altogether, these findings demonstrate that the approach we have applied is a powerful strategy to identify compounds with combined properties towards a chosen target. Our studies show how integration of chemistry, biology and computational analysis can provide robust strategies to identify new inhibitory scaffolds suitable for further development of anti-cancer targeted therapies.}},
    keywords = {Receptor tyrosine kinase; Met-antagonist; Neoplastic transformation; Chemical biological screening; Computer modelling},
    language = {English},
    affiliation = {Institut de Biologie du D{\'e}veloppement de Marseille Luminy - IBDML , ORPAILLEUR - INRIA Lorraine - LORIA},
    publisher = {Elsevier},
    pages = {184-189},
    journal = {Biochemical and Biophysical Research Communications / Biochemistry and Biophysics Research Communications},
    volume = {375},
    number = {2 },
    audience = {international },
    year = {2008},
}

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