Ras1 Inhibitors

Chemical inhibitors of Ras1 operate through several distinct mechanisms to impede the protein's function. Salirasib directly binds to the active GTP-bound form of Ras1, interfering with its ability to signal downstream effectors. This binding impedes Ras1's role in cellular signaling pathways, effectively inhibiting its function. Farnesylthiosalicylic acid employs a different strategy by displacing Ras1 from the cell membrane, disrupting its interaction with anchoring molecules necessary for its signaling function. This displacement leads to a reduction in Ras1-mediated signaling. In a similar vein, Lonafarnib and Tipifarnib target the enzyme farnesyltransferase, which is responsible for the post-translational modification of Ras1. By inhibiting this enzyme, these chemicals prevent Ras1 from undergoing farnesylation, a modification that is critical for its localization to the cell membrane and subsequent activation.

Furthermore, Sotorasib and Adagrasib are selective for the KRAS G12C mutant variant of Ras1, binding irreversibly and locking it in an inactive GDP-bound state. This action effectively halts the signaling pathways that Ras1 would normally activate. Deltarasin indirectly inhibits Ras1 by binding to phosphodiesterase δ, a protein that is essential for Ras1's transport to the plasma membrane. By blocking this transport, Deltarasin reduces the availability of Ras1 for signaling. BI-2852, MRTX849, and ARS-1620 all target Ras1 by binding to specific pockets on the protein, which are not involved in GDP/GTP binding, but are nonetheless critical for its activity. By binding to these sites, these inhibitors can prevent Ras1 from engaging in its normal function. BAY-293 disrupts the activation of Ras1 by targeting the SOS1/RAS interaction, which is necessary for Ras1 to exchange GDP for GTP, a key step in its activation process. Lastly, KO-947 inhibits ERK signaling, which is a downstream effector of Ras1. By hindering ERK signaling, KO-947 indirectly reduces Ras1's ability to propagate its signal, leading to inhibition of its overall activity within the cell.