Discovery of a Class of Potent and Selective Non‐competitive Sentrin‐Specific Protease 1 Inhibitors

Lindenmann, Urs; Brand, Michael; Gall, Flavio M.; Frasson, David; Hunziker, Lukas; Kroslakova, Ivana; Sievers, Martin; Riedl, Rainer

doi:10.1002/cmdc.202000067

Cited by 15 publications

(11 citation statements)

References 31 publications

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“…Triplotide and momordin Ic decrease the proliferation of LNCaP and PC3 cell lines and inhibit tumor growth in PC3 xenograft mice models. In addition, various synthetic inhibitors of SENP1 have been developed, including compound 38, compound J5, compound 4 (GN6958), compound 13m, and compounds 6, 7, and 10 [287][288][289][290][291]. However, in vivo data of synthetic SENP1 inhibitors in cancer models are lacking.…”

Section: Senp Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

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Section: Senp Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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“…SENP1 is now considered as a valid anticancer target, overexpressed in certain cancer (like non-small cell lung [127] and pancreatic [128] cancers) and a promotor of HCC [129]. Small molecules targeting SENP1 are actively searched [130][131][132].…”

Section: Discussionmentioning

confidence: 99%

Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

Goossens

Bailly

2021

Nat. Prod. Bioprospect.

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Biflavonoids are divided in two classes: C–C type compounds represented by the dimeric compound amentoflavone and C–O–C-type compounds typified by hinokiflavone (HNK) with an ether linkage between the two connected apigenin units. This later sub-group of bisflavonyl ethers includes HNK, ochnaflavone, delicaflavone and a few other dimeric compounds, found in a variety of plants, notably Selaginella species. A comprehensive review of the anticancer properties and mechanism of action of HNK is provided, to highlight the anti-proliferative and anti-metastatic activities of HNK and derivatives, and HNK-containing plant extracts. The anticancer effects rely on the capacity of HNK to interfere with the ERK1-2/p38/NFκB signaling pathway and the regulation of the expression of the matrix metalloproteinases MMP-2 and MMP-9 (with a potential direct binding to MMP-9). In addition, HNK was found to function as a potent modulator of pre-mRNA splicing, inhibiting the SUMO-specific protease SENP1. As such, HNK represents a rare SENP1 inhibitor of natural origin and a scaffold to design synthetic compounds. Oral formulations of HNK have been elaborated to enhance its solubility, to facilitate the compound delivery and to enhance its anticancer efficacy. The review shed light on the anticancer potential of C–O–C-type biflavonoids and specifically on the pharmacological profile of HNK. This compound deserves further attention as a regulator of pre-mRNA splicing, useful to treat cancers (in particular hepatocellular carcinoma) and other human pathologies.

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“…Hyper SUMOylation of target proteins plays a pivotal role in stress and pathogen responses and control of owering [71]. But Sentrinspeci c proteases (SENPs) are involved in the maturation and deconjugation of SUMO proteins from their substrate proteins in human [72]. Currently six different SENPs (SENP1, 2, 3, 5, 6, 7) have been identi ed in human [72].…”

Section: Discussionmentioning

confidence: 99%

Computational Discovery of a miRNA and its Putative Target Genes in Ziziphus Jujuba using Genome-wide Expressed Sequence Tags

Fernando

Zakeel

Safeena

2021

Preprint

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Background Ziziphus jujuba is an important fruit crop which is increasingly becoming popular among consumers due to its medicinal properties. Increasing worldwide demand for the fruit poses new challenges to the industry which includes the need for accelerated cultivar development of jujubes. To embark on cultivar development with improved traits such as high yield and disease resistance, molecular and conventional breeding, and genetic engineering become imperative. But inadequate trait-enhancing alleles or gene pleiotropism limit the direct use of several identified genes. To overcome these issues, microRNAs (miRNAs) can be utilized in breeding of jujubes as genetic modulators to fine-tune the regulation of gene expression, thus the discovery of miRNAs becomes important. Methods and results In this study using a computational approach, we identified one potential miRNA (zju-miR-215-3p) from 2904 expressed sequence tags. The miRNA showed down regulation of five target proteins (AP-2 complex subunit alpha, C2H2-type domain-containing protein, sentrin-specific protease 1, hydrolase_4 domain-containing protein and putative alpha-ketoglutarate-dependent dioxygenase) and their suppression appears to be helpful to the plant to overcome stress conditions. Conclusion The miRNA identified in this study is associated with five potential target proteins, most of which are implicated in metabolic and developmental processes associated with plant growth and reproduction. Future studies are necessary to validate the miRNA by RNA sequencing and to confirm the molecular functions of the down regulations of target proteins.

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Discovery of a Class of Potent and Selective Non‐competitive Sentrin‐Specific Protease 1 Inhibitors

Cited by 15 publications

References 31 publications

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

Computational Discovery of a miRNA and its Putative Target Genes in Ziziphus Jujuba using Genome-wide Expressed Sequence Tags

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