Kung Andrew L, Zabludoff Sonya D, France Dennis S, Freedman Steven J, Tanner Elizabeth A, Vieira Annelisa, Cornell-Kennon Susan, Lee Jennifer, Wang Beqing, Wang Jamin, Memmert Klaus, Naegeli Hans-Ulrich, Petersen Frank, Eck Michael J, Bair Kenneth W, Wood Alexander W, Livingston David M
Dana-Farber Cancer Institute and Harvard Medical School, Massachusetts 02115, USA.
Cancer Cell. 2004 Jul;6(1):33-43. doi: 10.1016/j.ccr.2004.06.009.
Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, we identified chetomin as a disrupter of HIF binding to p300. At a molecular level, chetomin disrupts the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacological attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small molecule.
在缺氧条件下，通过由缺氧诱导因子（HIF）途径介导的协调转录反应来维持体内平衡，这需要CBP和p300转录共激活因子的共同激活。通过基于靶点的高通量筛选，我们确定了chetomin是一种破坏HIF与p300结合的物质。在分子水平上，chetomin破坏了p300的CH1结构域的结构，并阻止其与HIF相互作用，从而减弱缺氧诱导的转录。chetomin的全身给药抑制了肿瘤内缺氧诱导的转录并抑制了肿瘤生长。这些结果证明了HIF活性的药理学减弱的治疗窗口，并进一步确立了通过小分子靶向转录共激活因子的功能来破坏信号转导途径的可行性。
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