Structure-activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding.
The synthesis of a series of berberine, phenantridine and isoquinoline derivatives was realized to explore their Rho GTPase nucleotide inhibitory activity. The compounds were evaluated in a nucleotide binding competition assay against Rac1, Rac1b, Cdc42 and in a cellular Rac GTPase activation assay. The insertion of 19 AA in the splice variant Rac1b is shown to be sufficient to introduce a conformational difference that allows compounds 4, 21, 22, and 26 to exhibit selective inhibition of Rac 1b over Rac1.
Beausoleil
Eric
E
Exonhit Therapeutics, 65 Boulevard Massena, F-75013 Paris, France. eric.beausoleil@exonhit.com
Chauvignac
Cédric
C
Taverne
Thierry
T
Lacombe
Sandrine
S
Pognante
Laure
L
Leblond
Bertrand
B
Pallares
Diego
D
Oliveira
Catherine De
CD
Bachelot
Florence
F
Carton
Rachel
R
Peillon
Hélène
H
Coutadeur
Séverine
S
Picard
Virginie
V
Lambeng
Nathalie
N
Désiré
Laurent
L
Schweighoffer
Fabien
F
D000595:Amino Acid Sequence; D001599:Berberine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009711:Nucleotides / Q000737:chemistry*; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009711:Nucleotides; D020033:Protein Isoforms; D001599:Berberine; D020830:rac1 GTP-Binding Protein; C039109:isoquinoline