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.