Inhibitors targeting the SUMOylation pathway: A patent review 2012‑2015 (Review)

Abstract

Small ubiquitin‑related modifier (SUMO) proteins bind to the lysine residue of target proteins to produce functionally mature proteins. The abnormal SUMOylation of certain target proteins is associated with diseases including cancer, heart disease, diabetes, arthritis, degenerative diseases and brain ischemia/stroke. Thus, there has been growing appreciation for the potential importance of the SUMO conjugation pathway as a target for treating these diseases. This review introduces the important steps in the reversible SUMOylation pathway. The SUMO inhibitors disclosed in the patents between 2012 and 2015 are divided into different categories according to their mechanisms of action. Certain compounds disclosed in this review have also been reported in other articles for their inhibition of the SUMOylation pathway following screening in cell lines. Although there are few studies using animal models or clinical trials that have used these compounds, the application of bortezomin, a ubiquitylation inhibitor, for treating cancer indicates that SUMO inhibitors may be clinically successful.

<p>Post-translational modifiers of liver kinase B1/serine/threonine kinase 11 in hepatocellular carcinoma</p>

“…In the near future, more research should focus on the study of the intermediates and players involved in these post-translational modifications of LKB1 in HCC. The recent advances on the development of pharmacological inhibitors of post-translational modifications, such as Pevonedistat, a specific inhibitor of NEDDylation,26 several small molecule inhibitors of the ubiquitination cascade,36 and inhibitors targeting the SUMO pathway37 further support these studies in order to find novel therapeutic targets to tackle HCC.

Figure 3Liver kinase B1 (LKB1) post-translational modifications in hepatocellular Carcinoma (HCC). In the last years, several evidence highlight that LKB1 expression is induced in HCC, a process that appears to be regulated at the post-translational level.

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Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities

“…Next, we examined the ability of GA in restoring Sp1 activity in cells overexpressing Sumo1. This experiment was intended to provide evidence related to the potential use of GA to reduce the effects of Sumoylation-mediated aberrant signaling responsible for pathobiology of cells and tissues [ 45 , 47 , 49 , 50 , 51 , 52 , 53 ]. mLECs were transfected with WT-Prdx6 promoter along with GFP-Vector or GFP-Sumo1 plasmid, and then treated with different concentrations of GA ( Figure 10 D) and BA ( Figure 10 E).…”

The post-translational modification, SUMOylation, and cancer (Review)

“…SUMOylation is upregulated significantly in the majority of cancers, and may thus be a potential target for cancer therapy. The SUMO pathways have profound impacts on protein-protein interactions and some SUMO inhibitors have been developed ( 208 , 209 ). However, a large number of clinical trials are warranted in order to verify these findings and provide useful information for the diagnosis and prognosis of cancer.…”