Discovery of\nNovel [1,2,4]Triazolo[1,5‑<i>a</i>]pyrimidine Derivatives\nas Novel Potent S‑Phase\nKinase-Associated Protein 2 (SKP2) Inhibitors for the Treatment of\nCancer

Skp1-CUL1-ROC1-F-box E3\nubiquitin ligases’ main component S-phase kinase-associated\nprotein 2 (Skp2) is responsible for specifically recognizing ubiquitination-modified\nsubstrates to be degraded such as p27 and p21 in the case of binding\nwith adaptor protein Cks1. Pharmacological inhibition of Skp2 has\nexhibited promising antitumor activity. Herein, we present the design\nand 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\nbinding of Skp2–Cks1. In addition, compound <b>E35</b> significantly inhibited colony formation and migration, as well\nas arrested the cell cycle at the S-phase. Mechanistically, compound <b>E35</b> markedly decreased the expression of Skp2, as well as\nincreased the expression of its substrates p21 and p27. Furthermore,\ncompound <b>E35</b> showed an obvious inhibitory effect on MGC-803\nxenograft mice without obvious toxicity. All of these results suggest\nthat compound <b>E35</b> might be a valuable lead compound for\nantitumor agents targeting Skp2.