title: Structure-activity relationship of isoform selective inhibitors of Rac1/1b GTPase nucleotide binding.
abstract: 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.
authors.affiliation: Exonhit Therapeutics, 65 Boulevard Massena, F-75013 Paris, France. eric.beausoleil@exonhit.com
authors.forename: Eric
authors.initials: E
authors.lastname: Beausoleil
authors.forename: Cédric
authors.initials: C
authors.lastname: Chauvignac
authors.forename: Thierry
authors.initials: T
authors.lastname: Taverne
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lacombe
authors.forename: Laure
authors.initials: L
authors.lastname: Pognante
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leblond
authors.forename: Diego
authors.initials: D
authors.lastname: Pallares
authors.forename: Catherine De
authors.initials: CD
authors.lastname: Oliveira
authors.forename: Florence
authors.initials: F
authors.lastname: Bachelot
authors.forename: Rachel
authors.initials: R
authors.lastname: Carton
authors.forename: Hélène
authors.initials: H
authors.lastname: Peillon
authors.forename: Séverine
authors.initials: S
authors.lastname: Coutadeur
authors.forename: Virginie
authors.initials: V
authors.lastname: Picard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambeng
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
authors.forename: Fabien
authors.initials: F
authors.lastname: Schweighoffer
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009711:Nucleotides; D020033:Protein Isoforms; D001599:Berberine; D020830:rac1 GTP-Binding Protein; C039109:isoquinoline