A small molecule disruptor of Rb/Raf-1 interaction inhibits cell proliferation, angiogenesis, and growth of human tumor xenografts in nude mice.
Although 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, Rb/Raf-1 disruptor 251 (RRD-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 anchorage-independent growth of human cancer cells and knockdown of Rb with short hairpin RNA or forced expression of E2F1 rescued cells from RRD-251-mediated growth arrest. P.o. 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 phosphorylated Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents.
Kinkade
Rebecca
R
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Dasgupta
Piyali
P
Carie
Adam
A
Pernazza
Daniele
D
Carless
Melanie
M
Pillai
Smitha
S
Lawrence
Nicholas
N
Sebti
Said M
SM
Chellappan
Srikumar
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; C556907:RRD 251; D016160:Retinoblastoma Protein; D019908:Proto-Oncogene Proteins c-raf; D013890:Thiourea