State 1(T) inhibitors of activated Ras.

Abstract

Oncogenic mutations in the Ras (rat sarcoma) protein lead to a permanent activation of the Ras pathway and are found in approximately 30% of all human tumors. During signal transduction, Ras is transiently activated by GTP binding and interacts with effector proteins such as Raf kinase. Ras complexed with GTP (T) occurs in at least two conformational states, states 1(T) and 2(T), where state 2(T) represents the true effector-interaction state and state 1(T) has only a low affinity for effectors. Stabilization of state 1(T) by small molecules such as metal-cyclens can reduce the affinity for effectors and thus it can lead to an interruption of the signal transduction chain. Metal-cyclens bind inside the nucleotide-binding pocket to GTP, shifting the conformational equilibrium of Ras toward state 1(T). In contrast, Zn(2+)-BPA (bis(2-picolyl)amine) binds outside the nucleotide-binding pocket but nevertheless allosterically stabilizes state 1(T) and thus inhibits Raf interaction. It shows a higher affinity for the oncogenic mutant Ras(G12V) than for wild type in contrast to other compounds such as Zn(2+)-cyclen.