Targeting SUMO signaling to wrestle cancer

The small ubiquitin-like modifier (SUMO) signaling cascade is critical for gene expression, genome integrity, and cell cycle progression. In this review, we discuss the important role SUMO may play in cancer and how to target SUMO signaling. Recently developed small molecule inhibitors enable therapeutic targeting of the SUMOylation pathway. Blocking SUMOylation not only leads to reduced cancer cell proliferation but also to an increased antitumor immune response by stimulating interferon (IFN) signaling, indicating that SUMOylation inhibitors have a dual mode of action that can be employed in the fight against cancer. The search for tumor types that can be treated with SUMOylation inhibitors is ongoing. Employing SUMO conjugation inhibitory drugs in the years to come has potential as a new therapeutic strategy.Cancer Signaling networks and Molecular Therapeutic

Computational study of SENP1 in cancer by novel natural compounds and ZINC database screening

Introduction: Sentrin-specific protease 1 (SENP1) is a protein whose main function is deSUMOylation. SENP1 inhibits apoptosis, and increases angiogenesis, estrogen and androgen receptor transcription and c-Jun transcription factor, proliferation, growth, cell migration, and invasion of cancer. The in vivo and in vitro studies also demonstrated which natural compounds, especially phytochemicals, minerals, and vitamins, prevent cancer. More than 3,000 plant species have been reported in modern medicine. Natural compounds have many anti-cancerous andanti-turmeric properties such as antioxidative, antiangiogenic, antiproliferative, and pro-apoptotic properties.Methods: In this study, we investigated the interaction of some natural compounds with SENP1 to inhibit its activity. We also screened the ZINC database including natural compounds. Molecular docking was performed, and toxicity of compounds was determined; then, molecular dynamics simulation (MDS) and essential dynamics (ED) were performed on natural compounds with higher free binding energies and minimal side effects. By searching in a large library, virtual screening of the ZINC database was performed using LibDock and CDOCKER, and the final top 20 compounds were allowed for docking against SENP1. According to the docking study, the top three leading molecules were selected and further analyzed by MDS and ED.Results: The results suggest that resveratrol (from the selected compounds) and ZINC33916875 (from the ZINC database) could be more promising SENP1 inhibitory ligands.Discussion: Because these compounds can inhibit SENP1 activity, then they can be novel candidates for cancer treatment. However, wet laboratory experiments are needed to validate their efficacy as SENP1 inhibitors

Discovery and Development of Small Molecule Probes for the SUMO protease SENP1, a Novel Target for Advanced Prostate Cancer Therapy

Androgen signaling through the androgen receptor (AR) is essential for normal growth and function of the prostate gland. In prostate cancer (PC), androgens provide the main proliferative drive for the disease, making androgen-deprivation one of the primary therapeutic strategies. Although initially effective, such treatments select for tumor cells that are able to sustain proliferation in a reduced androgen environment.  This allows for the emergence of castration resistant PC, an incurable disease where both the AR transcriptional program is subverted and cellular senescence is evaded. SUMOylation is a post-translational modification that regulates both of these processes. SUMOylation of AR inhibits both basal and androgen-stimulated transcription in a promoter context manner and enhanced global SUMO modification induces prostate cell senescence. Advanced PC cells evade these mechanisms at least in part through the upregulation of SENP1, a SUMO-specific cysteine protease that reverses SUMOylation. In addition, AR is a direct activator of the SENP1 gene, creating a self-reinforcing loop that promotes and sustains its own activity and PC progression. This dissertation is aimed at the discovery and development of small molecule inhibitors of SENP1 as the basis for novel prostate cancer therapeutics. Using a robust FRET-based assay, we defined the kinetic properties of SENP1 and its closest paralog SENP2. This analysis revealed significant product inhibition and a differential sensitivity to ionic strength. Using this assay, an extensive high-throughput screening campaign led to the identification of two structurally distinct inhibitor classes. Characterization of these compounds indicates that they display significant selectivity towards SENP1 relative to SENP2 and that they act in both a reversible and competitive manner. Furthermore, these compounds inhibit native full-length SENP1 acting on endogenous SUMOylated substrates. Notably, both groups of compounds are known to display activity as purinergic receptor antagonists. The remarkable parallel pharmacology to P2X1 receptors led to our discovery that ATP, the endogenous P2X ligand, is a SENP1 selective inhibitor. We have thus revealed a novel nucleotide mediated regulation of SENP1. Using a combination of mutagenesis, biochemical assays, and fluorescence and NMR spectroscopy, we have characterized the binding of inhibitors and identified key enzyme residues involved in the interactions as well as residues responsible for SENP isoform selectivity. These findings reveal that SENP1 harbors a unique binding site for nucleotides that can be targeted by small molecules. This knowledge can guide novel strategies for further inhibitor development for evaluation of the therapeutic efficacy of SENP1 inhibitors in advanced prostate cancer models.PHDChemical BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/140973/1/carriemn_1.pd

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

The small ubiquitin-like modifier (SUMO) pathway regulates the hallmark properties of cancer cells. Moreover, alterations in activity and in levels of SUMO machinery components have been observed in human cancer. Due to the reversible nature of this post-translational protein modification, the balance between SUMOylation and the removal of SUMO is critical. Early-phase clinical trials are currently evaluating the safety and efficacy of SUMO pathway inhibition in cancer patients. In this comprehensive review, we critically discuss the potential of targeting the SUMO pathway as a therapeutic option for cancer. </p

Advances in the Development of Shape Similarity Methods and Their Application in Drug Discovery

Molecular similarity is a key concept in drug discovery. It is based on the assumption that structurally similar molecules frequently have similar properties. Assessment of similarity between small molecules has been highly effective in the discovery and development of various drugs. Especially, two-dimensional (2D) similarity approaches have been quite popular due to their simplicity, accuracy and efficiency. Recently, the focus has been shifted toward the development of methods involving the representation and comparison of three-dimensional (3D) conformation of small molecules. Among the 3D similarity methods, evaluation of shape similarity is now gaining attention for its application not only in virtual screening but also in molecular target prediction, drug repurposing and scaffold hopping. A wide range of methods have been developed to describe molecular shape and to determine the shape similarity between small molecules. The most widely used methods include atom distance-based methods, surface-based approaches such as spherical harmonics and 3D Zernike descriptors, atom-centered Gaussian overlay based representations. Several of these methods demonstrated excellent virtual screening performance not only retrospectively but also prospectively. In addition to methods assessing the similarity between small molecules, shape similarity approaches have been developed to compare shapes of protein structures and binding pockets. Additionally, shape comparisons between atomic models and 3D density maps allowed the fitting of atomic models into cryo-electron microscopy maps. This review aims to summarize the methodological advances in shape similarity assessment highlighting advantages, disadvantages and their application in drug discovery