Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases

Chem Biol. 2012 Jun 22;19(6):699-710. doi: 10.1016/j.chembiol.2012.05.009.


Rho GTPases have been implicated in diverse cellular functions and are potential therapeutic targets. By virtual screening, we have identified a Rho-specific inhibitor, Rhosin. Rhosin contains two aromatic rings tethered by a linker, and it binds to the surface area sandwiching Trp58 of RhoA with a submicromolar Kd and effectively inhibits GEF-catalyzed RhoA activation. In cells, Rhosin specifically inhibited RhoA activity and RhoA-mediated cellular function without affecting Cdc42 or Rac1 signaling activities. By suppressing RhoA or RhoC activity, Rhosin could inhibit mammary sphere formation by breast cancer cells, suppress invasion of mammary epithelial cells, and induce neurite outgrowth of PC12 cells in synergy with NGF. Thus, the rational designed RhoA subfamily-specific small molecule inhibitor is useful for studying the physiological and pathologic roles of Rho GTPase.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Weight
  • Organic Chemicals / chemical synthesis
  • Organic Chemicals / chemistry
  • Organic Chemicals / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • rho GTP-Binding Proteins / antagonists & inhibitors*
  • rho GTP-Binding Proteins / metabolism


  • Enzyme Inhibitors
  • Organic Chemicals
  • rhosin
  • rho GTP-Binding Proteins