The Ras family of small GTPases (H-Ras, K-Ras, and N-Ras) function as molecular switches, cycling between a GTP-bound active state and a GDP-bound inactive state, to turn on downstream Raf protein kinases. This initiates complex signaling pathways involved in cell growth, differentiation, and apoptosis. Mutations leading to aberrant Ras activation are frequently associated with various human cancers. Kobe 2602 is a selective Ras inhibitor that blocks H-Ras GTP binding to c-Raf-1 (Ki = 149 μM). Kobe 2602 has been shown to inhibit both anchorage-dependent and -independent growth and to induce apoptosis of H-RasG12V-transformed NIH 3T3 cells (IC50 = 1.4-2 μM). At an oral dose of 80 mg/kg, it also exhibits antitumor activity in mice bearing a xenograft of human colon cancer SW480 cells expressing K-RasG12V.
