Small-molecule compounds inhibiting S-phase kinase-associated protein 2: A review

Abstract

S-phase kinase-associated protein 2 (Skp2) is a substrate-specific adaptor in Skp1-CUL1-ROC1-F-box E3 ubiquitin ligases and widely regarded as an oncogene. Therefore, Skp2 has remained as an active anticancer research topic since its discovery. Accordingly, the structure of Skp2 has been solved and numerous Skp2 inhibiting compounds have been identified. In this review, we would describe the structural features of Skp2, introduce the ubiquitination function of SCF^Skp2, and summarize the diverse natural and synthetic Skp2 inhibiting compounds reported to date. The IC₅₀ data of the Skp2 inhibitors or inhibiting compounds in various kinds of tumors at cellular levels implied that the cancer type, stage and pathological mechanisms should be taken into consideration when selecting Skp2-inhibiting compound for cancer treatment.

Keywords: E3 ubiquitin ligase; S-phase kinase-associated protein 2; SCFSkp2; cancer treatment; inhibitor.

FIGURE 1

Comparison of IC₅₀ values between structure-based Skp2 inhibitors and non-structure-based compounds in NSCLC and SCLC cell lines.

FIGURE 2

The RNA expression levels of Skp2 in various cell lines, and its correlation with IC₅₀ values of four Skp2 inhibiting compounds. A The RNA expression level of Skp2 in various cell lines in Human Protein Atlas database; B-E. The correlation between RNA expression level of Skp2 and IC₅₀ values of SZL-P1-41, MLN4924, Skpin C1, and Flavokawain A respectively. The RNA expression level data was collected from Human Protein Atlas database, and the IC₅₀ value data was collected from the references listed in Table 2.