While the monomeric form of CDK2 is inactive, the kinase becomes active, like many other CDKs, when it forms a functional, heterodimeric complex with one of its two regulatory partners – Cyclins A and E. This member of the cyclin-dependent kinase (CDK) family is involved in DNA synthesis, G1/S phase transition, and G2 progression modulation 1. These results thus identify an autophagic degradation mechanism of CDK2 protein and provide a potential avenue towards treating CDK2-dependent cancers.Ĭyclin-dependent kinase 2 (CDK2) is best known for the key role it plays during cell cycle progression. 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. Using this approach, homoharringtonine (HHT) shows high affinity to the PPI and strongly disrupts the interaction between CDK2 and cyclins. To target the potential druggable pockets, we perform a LIVS in silico screening of a library containing 1925 FDA approved drugs. In this report, we identify two potential druggable pockets located in the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. 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. 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. Cyclin-dependent kinase 2 (CDK2) complex is significantly over-activated in many cancers.
0 kommentar(er)
