Fig. 5.
Direct and indirect RAS inhibitors. RAS proteins are synthesized in the cytosol, and different covalent inhibitors of KRASG12C are currently in clinical trials (1). RAS functioning requires membrane anchorage, which can be achieved through farnesylation by farnesyltransferase (FTase) or geranylation by geranylgeranylprenyltransferase (GGTase). By inhibiting FTase or GGTase, RAS membrane anchoring is prevented and RAS function blocked (2). Inhibition of PTPN11 (3) or SOS1/2 (4) prevents RAS activation through upstream signaling.