Discovery of Novel 1,3-Diphenylpyrazine Derivatives as Potent S-Phase Kinase-Associated Protein 2 (Skp2) Inhibitors for the Treatment of Cancer

F-box protein S-phase kinase-associated protein 2 (Skp2)is a componentof cullin-RING ligases, which is responsible for recruiting and ubiquitinatingsubstrates and subsequently plays its proteolytic and non-proteolyticrole. High expression of Skp2 is frequently observed in multiple aggressivetumor tissues and associated with poor prognosis. Several of the Skp2inhibitors have been reported in the last decades; however, few ofthem have shown detailed structure-activity relationship (SAR)and potent bioactivity. Herein, based on the hit compound 11a from our in-house library, we optimize and synthesize a series ofnew 2,3-diphenylpyrazine-based inhibitors targeting the Skp2-Cks1interaction and further systematically study the SAR. Among them,compound 14i shows potent activity against the Skp2-Cks1interaction with an IC50 value of 2.8 mu M and againstPC-3 and MGC-803 cells with IC50 values of 4.8 and 7.0 mu M, respectively. Most importantly, compound 14i exhibited effectively anticancer effects on PC-3 and MGC-803 xenograftmice models without obvious toxicity.

Automated summary

Skp2 is a component of cullin-RING ligases, and its high expression is associated with aggressive tumor tissues and poor prognosis. In this study, a series of new Skp2 inhibitors were synthesized and their structure-activity relationship was systematically studied. Among them, compound 14i showed potent activity against Skp2 and exhibited effective anticancer effects on PC-3 and MGC-803 cells as well as xenograft mouse models.