SENP Proteases as Potential Targets for Cancer Therapy

SIMPLE SUMMARY: Post-translational modification—the biochemical addition of functional groups or proteins—occurs following protein biosynthesis and contributes to an increase in the functional diversity of the proteome. Post-translational modifications include SUMOylation—the covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SUMOylation is a reversible modification, which is erased by SUMO-specific proteases (SENPs). Deregulation of SENPs leads to cellular dysfunction and is associated with various diseases, including cancer. The role of SENPs in cancer pathogenesis is expected, and thus these proteins are considered promising targets for drug design and development. In this review, we will discuss the role of SENPs, focusing on DNA repair and the cell cycle—cellular pathways malfunctioning in most cancer cells—and provide an update on advances in the development of SENP-oriented inhibitors. ABSTRACT: SUMOylation is a reversible post-translational modification (PTM) involving a covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SUMO-specific proteases (SENPs) are cysteine proteases with isopeptidase activity facilitating the de-conjugation of SUMO proteins and thus participating in maintaining the balance between the pools of SUMOylated and unSUMOylated proteins and in SUMO recycling. Several studies have reported that SENPs’ aberrant expression is associated with the development and progression of cancer. In this review, we will discuss the role of SENPs in the pathogenesis of cancer, focusing on DNA repair and the cell cycle—cellular pathways malfunctioning in most cancer cells. The plausible role of SENPs in carcinogenesis resulted in the design and development of their inhibitors, including synthetic protein-based, peptide-based, and small molecular weight inhibitors, as well as naturally occurring compounds. Computational methods including virtual screening have been implemented to identify a number of lead structures in recent years. Some inhibitors suppressed the proliferation of prostate cancer cells in vitro and in vivo, confirming that SENPs are suitable targets for anti-cancer treatment. Further advances in the development of SENP-oriented inhibitors are anticipated toward SENP isoform-specific molecules with therapeutic potential.