Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells.
Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells.
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DOI：
10.1038/s41467-022-30264-0
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发表时间：
2022-05-20
影响因子：
16.6
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文献类型：
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细胞周期蛋白依赖性激酶2（CDK 2）复合物在许多癌症中显著过度活化。虽然它使CDK 2成为癌症治疗的一个有吸引力的靶点，但大多数针对CDK 2的抑制剂都是ATP竞争剂，它们要么是非特异性的，要么是高毒性的，并且通常在临床试验中失败。一种替代方法是开发非ATP竞争性抑制剂;它们破坏CDK 2与其伴侣或底物之间的相互作用，导致特异性抑制CDK 2活性。在这份报告中，我们确定了两个潜在的药物口袋位于蛋白质-蛋白质相互作用界面（PPI）之间的CDK 2和细胞周期蛋白A。为了瞄准潜在的药物口袋，我们对包含1925种FDA批准的药物的库进行了LIVS计算机筛选。使用这种方法，高三尖杉酯碱（HHT）显示出对PPI的高亲和力，并强烈破坏CDK 2和细胞周期蛋白之间的相互作用。此外，我们证明，HHT诱导自噬降解的CDK 2蛋白通过三方基序21（Trim 21）在癌细胞中，这是证实了在白血病小鼠模型和人类原发性白血病细胞。因此，这些结果确定了CDK 2蛋白的自噬降解机制，并提供了治疗CDK 2依赖性癌症的潜在途径。CDK 2可以驱动癌细胞的增殖。在这里，作者筛选了CDK 2/cylinA复合物的非ATP竞争性抑制剂，发现高三尖杉酯碱可以破坏复合物并促进CDK 2的降解。
Cyclin-dependent kinase 2 (CDK2) complex is significantly over-activated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors against CDK2 are ATP competitors that are either nonspecific or highly toxic, and typically fail clinical trials. One alternative approach is to develop non-ATP competitive inhibitors; they disrupt interactions between CDK2 and either its partners or substrates, resulting in specific inhibition of CDK2 activities. In this report, we identify two potential druggable pockets located in the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target the potential druggable pockets, we perform a LIVS in silico screening of a library containing 1925 FDA approved drugs. Using this approach, homoharringtonine (HHT) shows high affinity to the PPI and strongly disrupts the interaction between CDK2 and cyclins. Further, we demonstrate that HHT induces autophagic degradation of the CDK2 protein via tripartite motif 21 (Trim21) in cancer cells, which is confirmed in a leukemia mouse model and in human primary leukemia cells. These results thus identify an autophagic degradation mechanism of CDK2 protein and provide a potential avenue towards treating CDK2-dependent cancers. CDK2 can drive the proliferation of cancer cells. Here, the authors screened for a non-ATP competitive inhibitor of the CDK2/cylinA complex and find that Homoharringtonine can disrupt the complex and promote the degradation of CDK2.
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影响因子：
--
作者：
Herrero-Ruiz J;Mora-Santos M;Giráldez S;Sáez C;Japón MA;Tortolero M;Romero F
通讯作者：
Romero F
DOI：
10.1083/jcb.201503023
发表时间：
2015-09-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kimura T;Jain A;Choi SW;Mandell MA;Schroder K;Johansen T;Deretic V
通讯作者：
Deretic V
影响因子：
2.1
作者：
Gannon, JV;Nebreda, A;Hunt, T
通讯作者：
Hunt, T
影响因子：
3.1
作者：
Esposito, Luca;Indovina, Paola;Giordano, Antonio
通讯作者：
Giordano, Antonio
AI26 抑制 ADP-核糖基水解酶 ARH3 并抑制 DNA 损伤修复
影响因子：
4.8
作者：
Liu, Xiuhua;Xie, Rong;Yu, Xiaochun
通讯作者：
Yu, Xiaochun