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

Rebecca Kinkade, Piyali Dasgupta, Adam Carie, Daniele Pernazza, Melanie Carless, Smitha Pillai, Nicholas Lawrence, Said M. Sebti, Srikumar Chellappan

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    42 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)3810-3818
    Number of pages9
    JournalCancer Research
    Volume68
    Issue number10
    DOIs
    StatePublished - May 15 2008

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Kinkade, R., Dasgupta, P., Carie, A., Pernazza, D., Carless, M., Pillai, S., Lawrence, N., Sebti, S. M., & Chellappan, S. (2008). A small molecule disruptor of Rb/Raf-1 interaction inhibits cell proliferation, angiogenesis, and growth of human tumor xenografts in nude mice. Cancer Research, 68(10), 3810-3818. https://doi.org/10.1158/0008-5472.CAN-07-6672