Skp2 inhibitor C1 is a specific small molecule inhibitor of Skp2-mediated p27 degradation, selectively inhibited Skp2-mediated p27 degradation by reducing p27 binding through key compound-receptor contacts.
Skp2 is frequently overexpressed in many human cancers and plays a key role in tumorigenesis. As a component of the SCFSkp2 ubiquitin E3 ligase complex, Skp2 is responsible for recruiting substrate proteins for their ubiquitination and subsequent degradation by the 26S proteasome. Thus, Skp2 promotes the cell cycle by down-regulating cell cycle proteins such as the tumor suppressor p27[3]. Skp2 inhibitor C1 is a highly selective small molecule Inhibitor of Skp2-mediated p27 degradation[4]. T47D cells treated with C1 (5 μM for 16 hours) displayed an increase in G1 phase (p < 0.0001) and a decrease in S phase (p < 0.0001), correlating with p27 protein induction. In contrast, MCF-7 cells responded to C1 with a significant reduction in G1 phase (35%, p < 0.0001) and an increase in G2-M phase (43%, p < 0.0001). This G1 reduction and G2/M arrest is dose dependent on C1 and correlates with increased p27 protein levels[4].
作用机制
Skp2 Inhibitor C1 inhibits Skp2-mediated p27 degradation by either forming predicted electrostatic interactions with Cks1-Q52 and/or hydrogen bonding to Cks1-R44 or Skp2-R344.
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