Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases.

Abstract

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.

• Authors: Xun Shang, Fillipo Marchioni, Nisha Sipes, Chris R Evelyn, Moran Jerabek-Willemsen, Stefan Duhr, William Seibel, Matthew Wortman, Yi Zheng
• Journal: Chemistry & biology (Chem Biol) Vol. 19 Issue 6 Pg. 699-710 (Jun 22 2012) ISSN: 1879-1301 [Electronic] United States
• PMID: 22726684 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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