A new Met inhibitory-scaffold identified by a focused forward chemical biological screen.
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.
Patané
Salvatore
S
Developmental Biology Institute of Marseille-Luminy (IBDML), UMR 6216 CNRS, INSERM, Université de la Méditerrannée, Campus de Luminy-Case 907, 13288 Marseille Cedex 09, France.
Pietrancosta
Nicolas
N
Hassani
Hessameh
H
Leroux
Vincent
V
Maigret
Bernard
B
Kraus
Jean-Louis
JL
Dono
Rosanna
R
Maina
Flavio
F
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D005464:Fluorobenzenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D005464:Fluorobenzenes; C531428:JLK1360; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met