Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases.
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.
Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Xun
X
Shang
Fillipo
F
Marchioni
Nisha
N
Sipes
Chris R
CR
Evelyn
Moran
M
Jerabek-Willemsen
Stefan
S
Duhr
William
W
Seibel
Matthew
M
Wortman
Yi
Y
Zheng
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008970:Molecular Weight; D009930:Organic Chemicals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D009930:Organic Chemicals; C586690:rhosin; D020741:rho GTP-Binding Proteins