期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30264-0
关键词
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资金
- National Cancer Institute [NCI 2R01CA139158]
- National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK R01DK124627]
- National Key R&D Program of China [2018YFA0800100, 2018YFA0800102]
- National Natural Science Foundation of China [32070630, 31970555]
- National Cancer Institute of the National Institutes of Health [P30CA33572]
CDK2 is over-activated in many cancers and is a potential target for cancer therapy. The authors identified a non-ATP competitive inhibitor, Homoharringtonine, that disrupts the interaction between CDK2 and cyclins and induces autophagic degradation of CDK2 protein. This study provides insights into a potential mechanism for 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. 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.
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