Disrupting the Rb-Raf-1 interaction: a potential therapeutic target for cancer.
Cell-cycle progression in cancer is often mediated by disrupting the function of the retinoblastoma tumor suppressor protein, Rb. One way in which Rb's function is altered is through phosphorylation mediated by cyclin-dependent kinases (CDKs). Our studies have shown that the Raf-1 kinase binds and phosphorylates Rb very early in the cell cycle prior to the binding of cyclins and CDKs. It was also found that human lung cancer tumor samples had increased binding of Raf-1 to Rb, suggesting this interaction could have contributed to the malignancy of these tumors. Disrupting the Rb-Raf-1 interaction could inhibit cell proliferation in a multitude of cancer cell lines as well as prevent angiogenesis and tumor growth in vivo. Thus, the Rb-Raf-1 interaction is a promising therapeutic target for cancer. This review will highlight the importance of the Rb-Raf-1 interaction in cancer, the search for small molecules capable of disrupting the interaction as well as properties of Rb-Raf-1 disruptors, focusing specifically on RRD-251 (Rb-Raf-1 Disruptor 251). This review will also touch on why targeting protein-protein interactions may be a viable alternate and better strategy to inhibiting kinase function for cancer therapies.
Davis
Rebecca K
RK
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Chellappan
Srikumar
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D016160:Retinoblastoma Protein; D019908:Proto-Oncogene Proteins c-raf