Synthesis and Evaluation of Ginkgolic Acid Derivatives as SUMOylation Inhibitors

Brackett, Christopher M.; García-Casas, Ana; Castillo-Lluva, Sonia; Blagg, Brian S. J.

doi:10.1021/acsmedchemlett.0c00353

Cited by 14 publications

(12 citation statements)

References 22 publications

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“…Recent advances in the development of synthetic inhibitors have enabled more specific and efficient targeting of the SUMO pathway. Synthetic inhibitors of SAE include compound 9, compound 21, various pyrazole and thiazole urea-containing compounds, ML-792, COH000, ML-93, several ginkgolic acid derivatives, and most recently, TAK-981 [267][268][269][270][271][272][273][274][275]. For example, compound 21 and COH000 act in a similar way as the natural SAE inhibitors.…”

Section: Sumo E1 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: Sumo E1 Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Kukkula

Ojala

Mendez

et al. 2021

Cancers

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“…Brackett et al synthesized ginkgolic acid derivatives with 6–17 carbon chains to reveal the SAR for SUMO E1. 357 The results showed that any alteration of the substitution pattern about the central aromatic ring completely ablated SUMOylation inhibition. All 2,6-disubstituted analogs could inhibit RanGAP1 SUMOylation at the 50 μM concentration, suggesting that unsaturation did not exert a negative effect on SUMOylation inhibition.…”

Section: Bioactivitymentioning

confidence: 96%

“…In addition, a long alkyl chain is required for ginkgolic acid derivatives to inhibit SUMO E1 and an optimal alkyl tail length is 11–13 (6- and 8-carbon analogs were inactive). 357 Ginkgo polysaccharides displayed antitumor activity against SMMC-7721 hepatoma cells, 358 human SGC-7901 gastric cancer cells, 359 and human bladder T24 cancer cells. In addition, a selenium (Se)-containing polysaccharide was isolated and found to induce bladder cancer apoptosis, likely through a mitochondria-dependent pathway.…”

Section: Bioactivitymentioning

confidence: 99%

“…356 Interestingly, ginkgolic acid was one of the first natural products identified as an inhibitor of the SUMO E1 enzyme. 357 SUMOylation is an important post-translational modification that has been shown to modulate protein activity associated with various signaling pathways, and represents an important therapeutic target. Nevertheless, little progress has been made toward the development of more selective and potent SUMOylation inhibitors.…”

Section: Bioactivitymentioning

confidence: 99%

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Structure, synthesis, biosynthesis, and activity of the characteristic compounds fromGinkgo bilobaL.

Liu

Gao

et al. 2022

Nat. Prod. Rep.

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“…To determine this, we investigated the effect of ginkgolic acid (GA). GA, an extract from Ginkgo biloba leaves, is a type of alkyl phenol that can directly bind SUMO-activating enzyme, E1, and inhibit the formation of the E1-SUMO intermediate, thereby diminishing SUMOylation [136][137][138][139][140]. Because SUMO1 depletion enhanced autophagic activities in HD, we hypothesized that GA might enhance the autophagy activities and alter HTT levels in HD cells.…”

Section: The Sumoylation Inhibitor Ginkgolic Acid (Ga) Enhances Autopmentioning

confidence: 99%

Deletion of Small Ubiquitin-like Modifier-1 Attenuates Behavioral and Anatomical Deficits by Enhancing Functional Autophagic Activities in Huntington Disease

Ramírez-Jarquín

Sharma

Shahani

et al. 2021

Preprint

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Mutant HTT (mHTT) associated with Huntington disease (HD) affects the central nervous system by prominent atrophy in the striatum and promotes psychiatric, cognitive, and choreiform movements, although the exact mechanism remains obscure. Previous studies have shown that SUMO1 (Small Ubiquitin-like Modifier-1) modification of mHTT promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knock-in mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions, while increasing cytoplasmic inclusions in the striatum of HD mice. SUMO1 deletion also enhanced autophagic activity, characterized by augmented interactions between mHTT inclusions and a lysosomal marker (LAMP1), increased LC3B/LAMP1 interaction, and decreased sequestosome-1 (p62) and mHTT and diminished p62/LAMP1 interactions in DARPP-32 positive medium spiny neurons (MSNs) in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by improving autophagy activities.

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Synthesis and Evaluation of Ginkgolic Acid Derivatives as SUMOylation Inhibitors

Cited by 14 publications

References 22 publications

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Structure, synthesis, biosynthesis, and activity of the characteristic compounds fromGinkgo bilobaL.

Deletion of Small Ubiquitin-like Modifier-1 Attenuates Behavioral and Anatomical Deficits by Enhancing Functional Autophagic Activities in Huntington Disease

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