Discovery of Novel [1,2,4]Triazolo[1,5-<i>a</i>]pyrimidine Derivatives as Novel Potent S-Phase Kinase-Associated Protein 2 (SKP2) Inhibitors for the Treatment of Cancer

Skp1-CUL1-ROC1-F-box E3 ubiquitin ligases' main component S-phase kinase-associated protein 2 (Skp2) is responsible for specifically recognizing ubiquitination-modified substrates to be degraded such as p27 and p21 in the case of binding with adaptor protein Cks1. Pharmacological inhibition of Skp2 has exhibited promising antitumor activity. Herein, we present the design and optimization of a series of [1,2,4]triazolo[1,5-<i>a</i>]pyrimidine-based small molecules targeting Skp2. Among them, <b>E35</b> demonstrated excellent inhibitory activities against the binding of Skp2-Cks1. In addition, compound <b>E35</b> significantly inhibited colony formation and migration, as well as arrested the cell cycle at the S-phase. Mechanistically, compound <b>E35</b> markedly decreased the expression of Skp2, as well as increased the expression of its substrates p21 and p27. Furthermore, compound <b>E35</b> showed an obvious inhibitory effect on MGC-803 xenograft mice without obvious toxicity. All of these results suggest that compound <b>E35</b> might be a valuable lead compound for antitumor agents targeting Skp2.