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靶向 CDK9 可重新激活癌症中的表观遗传沉默基因。
Cell ( IF 42.5 ) Pub Date : 2018-Nov-15 , DOI: 10.1016/j.cell.2018.09.051 Hanghang Zhang , Somnath Pandey , Meghan Travers , Hongxing Sun , George Morton , Jozef Madzo , Woonbok Chung , Jittasak Khowsathit , Oscar Perez-Leal , Carlos A. Barrero , Carmen Merali , Yasuyuki Okamoto , Takahiro Sato , Joshua Pan , Judit Garriga , Natarajan V. Bhanu , Johayra Simithy , Bela Patel , Jian Huang , Noël J.-M. Raynal , Benjamin A. Garcia , Marlene A. Jacobson , Cigall Kadoch , Salim Merali , Yi Zhang , Wayne Childers , Magid Abou-Gharbia , John Karanicolas , Stephen B. Baylin , Cynthia A. Zahnow , Jaroslav Jelinek , Xavier Graña , Jean-Pierre J. Issa
Cell ( IF 42.5 ) Pub Date : 2018-Nov-15 , DOI: 10.1016/j.cell.2018.09.051 Hanghang Zhang , Somnath Pandey , Meghan Travers , Hongxing Sun , George Morton , Jozef Madzo , Woonbok Chung , Jittasak Khowsathit , Oscar Perez-Leal , Carlos A. Barrero , Carmen Merali , Yasuyuki Okamoto , Takahiro Sato , Joshua Pan , Judit Garriga , Natarajan V. Bhanu , Johayra Simithy , Bela Patel , Jian Huang , Noël J.-M. Raynal , Benjamin A. Garcia , Marlene A. Jacobson , Cigall Kadoch , Salim Merali , Yi Zhang , Wayne Childers , Magid Abou-Gharbia , John Karanicolas , Stephen B. Baylin , Cynthia A. Zahnow , Jaroslav Jelinek , Xavier Graña , Jean-Pierre J. Issa
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细胞周期蛋白依赖性激酶 9 (CDK9) 通过 RNAPII 暂停释放促进转录延伸。我们现在报告 CDK9 对于维持异染色位点的基因沉默也是必不可少的。通过具有遗传确认的活细胞药物筛选，我们发现 CDK9 抑制可重新激活癌症中表观遗传沉默的基因，从而恢复肿瘤抑制基因的表达、细胞分化和内源性逆转录病毒基因的激活。CDK9 抑制使 SWI/SNF 蛋白 BRG1 去磷酸化，这有助于基因重新激活。通过基因表达优化，我们开发了一种高选择性 CDK9 抑制剂（MC180295，IC50 = 5 nM），它在体外具有广泛的抗癌活性，并且在体内癌症模型中有效。此外，CDK9 抑制在体内对免疫检查点抑制剂 α-PD-1 敏感，
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更新日期：2018-10-26
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