Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases

摘要: Rho family GTPases (including Rac, and Cdc42) collectively control cell proliferation, adhesion migration are of interest as functional therapeutic targets in numerous epithelial cancers. Based on high throughput screening the Prestwick Chemical Library® cheminformatics we identified R-enantiomers two approved drugs (naproxen ketorolac) inhibitors Rac1 Cdc42. The corresponding S-enantiomers considered active component racemic drug formulations, acting non-steroidal anti-inflammatory (NSAIDs) with selective activity against cyclooxygenases. Here, show that naproxen ketorolac inactive GTPases. Additionally, more than twenty other NSAIDs lacked inhibitory action GTPases, establishing selectivity NSAIDs. R-naproxen was first a lead compound tested parallel its S-enantiomer non-chiral 6-methoxy-naphthalene acetic acid (active metabolite nabumetone, another NSAID) structural series. Cheminformatics-based substructure analyses—using rotationally constrained carboxylate R-naproxen—led to identification [R/S] suitable FDA-approved candidate. Cell based measurement GTPase (in animal human lines) demonstrated specifically inhibit epidermal growth factor stimulated Cdc42 activation. effects cells largely mimic those established (NSC23766) (CID2950007/ML141) specific inhibitors. Docking predicts rotational constraints position moieties preferentially coordinate magnesium ion, thereby destabilizing nucleotide binding can be docked but less favorably positioned proximity magnesium. R-ketorolac have potential for rapid translation efficacy treatment several cancer types account toxicity profiles novel activities Rho-family