Fig. 1. Identification of a disruptor of CDK2 complex.

A Druggability prediction for CDK2/Cyclin A complex by CavityPlus. Three druggable pockets identified from the CDK2-CyclinA complex (PDB code: 1FIN). The cartoon illustrated the structures of CDK2 and Cyclin A, which were mainly colored in lemon and deep teal, respectively. Within the CDK2 subunit, the C-helix (residues: 47–57) and activation segment (residues: 145–172) were highlighted in red and purple, respectively. Surfaces of the highly druggable pockets were colored in deep salmon, marine, light orange. Among them, the pocket highlighted in light orange was the known ATP-binding pocket. B Virtual ligand screening procedure based on CDK2/Cyclin A complex structure. The left panel was the CDK2/Cyclin A complex structure and virtual screening compounds. FDA-approved drug molecules from LIVS virtual screening pipeline were shown as yellow lines (HHT is colored blue) on CDK2 surface (hydrophobic surface is displayed as red). Cyclin A protein was displayed as a gray cartoon. C DARTS assay to identify the interaction between HHT and CDK2 with the incubation of HHT at 0, 1, 10, 100 μg/mL separately. D Pulldown assay by HHT-conjugated magnetic beads. E Pulldown assay by HHT-conjugated magnetic beads with the co-incubation of either DMSO, HHT (1 μg/mL), or Rosconvitine (50 μM). F Binding mode of HHT with CDK2. HHT forms hydrogen bonds (yellow dots) with T47, R50, and R150 in CDK2. G Pulldown assay by HHT-conjugated magnetic beads with purified GST-CDK2 or GST-CDK2-3As proteins. H Co-immunoprecipitation by CDK2 antibody after THP1 cells treated with different doses of HHT as indicated for 3 hours. I Representative western blots of indicated proteins in THP1 cells after HHT treatment for 24 hours. All the western-blotting results shown here were representative of three independent experiments. Source data are provided as a Source data file.