Two best described drugs with Rac1 inhibitory capacity: cholesterol-lowering statins and immunosuppressive azathioprine and 6-mercaptopurine and mechanisms of Rac1 inhibition
| Mechanism of Rac1 Inhibition |
|---|
| Statins |
| INDIRECT |
| Downregulation of cholesterol synthesis by statins decreases the intermediate isoprenoid metabolite geranylgeranyl pyrophosphate, which is the substrate for the enzyme geranylgeranyl transferase-1. GGTase-1 transfers geranylgeranyl to specific motifs on RhoA and Rac1, altering GTPase activity. |
| Statins induce small GTP-binding protein dissociation stimulator upregulation, which leads to enhanced Rac1 degradation. |
| Statin treatment induces shear stress–responsive transcription factor KLF2 expression and thereby ERK5 activation, which strongly decreases PAK1 mRNA and protein expression and thereby Rac1-mediated signaling. |
| Azathioprine or 6-mercaptopurine |
| DIRECT |
| Azathioprine- or 6-mercaptopurine–derived metabolites 6-thio-GDP and 6-thio-GTP are thought to bind directly to Rac1 and block Rac1 activation. |
| Note: Both azathioprine and 6-mercaptopurine disturb the purine biosynthesis pathway. Thus, next to the GMP pathway, 6-thio-AMP, -ADP, and -ATP are also generated and are not involved in Rac1 inhibition. |