Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells

Jiawei Zhang, Yichao Gan, Hongzhi Li, Jie Yin, Xin He, Liming Lin, Senlin Xu, Zhipeng Fang, Byung-wook Kim, Lina Gao, Lili Ding, Eryun Zhang, Xiaoxiao Ma, Junfeng Li, Ling Li, Yang Xu, David Horne, Rongzhen Xu, Hua Yu, Ying Gu () and Wendong Huang ()
Additional contact information
Jiawei Zhang: Zhejiang University
Yichao Gan: Zhejiang University
Hongzhi Li: Beckman Research Institute
Jie Yin: Zhejiang University
Xin He: Beckman Research Institute
Liming Lin: Zhejiang University
Senlin Xu: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute
Zhipeng Fang: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute
Byung-wook Kim: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute
Lina Gao: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute
Lili Ding: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute
Eryun Zhang: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute
Xiaoxiao Ma: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute
Junfeng Li: Beckman Research Institute of the City of Hope
Ling Li: Beckman Research Institute
Yang Xu: Zhejiang University
David Horne: Beckman Research Institute
Rongzhen Xu: Zhejiang University
Hua Yu: Beckman Research Institute of the City of Hope
Ying Gu: Zhejiang University
Wendong Huang: Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30264-0

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