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 0065 is an orally active Ras inhibitor with selectivity for H-Ras (Ki = 46 μM). It can inhibit both anchorage-dependent and -independent growth and induce apoptosis of H-RasG12V-transformed NIH 3T3 cells (IC50 = ~1.5 μM), which leads to a down-regulation of MEK/ERK, Akt, RalA, and Son of sevenless. At an oral dose of 80 mg/kg, Kobe 0065 also exhibits antitumor activity in mice bearing a xenograft of human colon cancer SW480 cells expressing K-RasG12V.
