A small molecule disruptor of Rb/Raf-1 interaction inhibits cell proliferation, angiogenesis, and growth of human tumor xenografts in nude mice
A small molecule disruptor of Rb/Raf-1 interaction inhibits cell proliferation, angiogenesis, and growth of human tumor xenografts in nude mice
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DOI：
10.1158/0008-5472.can-07-6672
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发表时间：
2008-05-15
期刊：
影响因子：
11.2
通讯作者：
Chellappan, Srikumar
中科院分区：
文献类型：
--
作者：
Kinkade, Rebecca;Dasgupta, Piyali;Chellappan, Srikumar
尽管细胞周期蛋白依赖性激酶磷酸化并使 Rb 失活这一点已得到充分证实，但 Raf-1 激酶与 Rb 发生物理相互作用，并在细胞周期早期启动磷酸化级联反应。我们已经鉴定出一种口服活性小分子 Rb/Raf-1 破坏剂 251 (RRD-251)，它能有效且选择性地破坏 Rb/Raf-1，但不破坏 Rb/E2F、Rb/抑制素、Rb/细胞周期蛋白 E 和 Rb/HDAC 结合。选择性抑制 Rb/Raf-1 结合可抑制 Rb 将 Raf-1 招募至增殖启动子的能力，并抑制 E2F1 依赖性转录活性。 RRD-251 抑制人类癌细胞的贴壁依赖性和贴壁非依赖性生长，并且用短发夹 RNA 敲低 Rb 或强制表达 E2F1 将细胞从 RRD-251 介导的生长停滞中拯救出来。邮政信箱对小鼠进行治疗仅在具有功能性 Rb 的肿瘤中导致显着的肿瘤生长抑制，并且伴随着血管生成的抑制、增殖的抑制、磷酸化 Rb 水平的降低以及体内 Rb/Raf-1 的抑制，但不包括 Rb/E2F1 的结合。因此，选择性靶向 Rb/Raf-1 相互作用似乎是开发新型化疗药物的一种有前途的方法。
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.