A small molecule disruptor of Rb-Raf-1 interaction inhibits cell proliferation angiogenesis and growth of human tumor xenografts in nude mice

摘要

Though it is well established that cyclin-dependent kinases phosphorylate and inactivate Rb, the Raf-1 kinase physically interacts with Rb and initiates the phosphorylation cascade early in the cell cycle. We have identified an orally-active small molecule, RRD-251 (Rb – Raf-1 Disruptor 251), that potently and selectively disrupts the Rb/Raf-1 but not Rb/E2F, Rb/Prohibitin, Rb/Cyclin E and Rb/HDAC binding. The selective inhibition of Rb/Raf-1 binding suppressed the ability of Rb to recruit Raf-1 to proliferative promoters and inhibited E2F1-dependent transcriptional activity. RRD-251 inhibited anchorage-dependent and –independent growth of human cancer cells; and knockdown of Rb with shRNA or forced expression of E2F1 rescued from RRD251-mediated growth arrest. Oral treatment of mice resulted in significant tumor growth suppression only in tumors with functional Rb; and this was accompanied by inhibition of angiogenesis, inhibition of proliferation, decreased phospho-Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb-Raf-1 interaction appears to be a promising approach for developing novel chemotherapeutic agents.