Small-molecule inhibitors targeting small ubiquitin-like modifier pathway for the treatment of cancers and other diseases

Hua, D.; Wu, Xiaoxing

doi:10.1016/j.ejmech.2022.114227

Cited by 4 publications

(2 citation statements)

References 134 publications

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“…There are few studies on agonists or inhibitors related to other PTMs, for example, ubiquitination, glycosylation, sumoylation, oxidation, carbonylation, which are also critical in regulation of STING. There have been developed many reviews about targeted therapy of ubiquitination (162)(163)(164), glycosylation (165), sumoylation (166), oxidation (167). More studies could focus on the role of these agonists and inhibitors in regulating STING pathway, proposing more comprehensive therapeutic strategies to improve STING-related diseases.…”

Section: Ptms Targeted Therapymentioning

confidence: 99%

Post-Translational Modifications of STING: A Potential Therapeutic Target

Kang

Liu

et al. 2022

Front. Immunol.

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Stimulator of interferon genes (STING) is an endoplasmic-reticulum resident protein, playing essential roles in immune responses against microbial infections. However, over-activation of STING is accompanied by excessive inflammation and results in various diseases, including autoinflammatory diseases and cancers. Therefore, precise regulation of STING activities is critical for adequate immune protection while limiting abnormal tissue damage. Numerous mechanisms regulate STING to maintain homeostasis, including protein-protein interaction and molecular modification. Among these, post-translational modifications (PTMs) are key to accurately orchestrating the activation and degradation of STING by temporarily changing the structure of STING. In this review, we focus on the emerging roles of PTMs that regulate activation and inhibition of STING, and provide insights into the roles of the PTMs of STING in disease pathogenesis and as potential targeted therapy.

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Section: Ptms Targeted Therapymentioning

confidence: 99%

Post-Translational Modifications of STING: A Potential Therapeutic Target

Kang

Liu

et al. 2022

Front. Immunol.

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“…The first small molecule inhibitors reported in 2011 were also covalent inhibitors targeting the catalytic site resulting in two-digit micromolar inhibitors ( 1 – 3 ) ( Figure 1 ) [ 19 , 20 ]. Later, non-covalent inhibitors ( 4 – 10 ) for SENP1 were developed [ 21 , 22 , 23 , 24 , 25 , 26 ], with the most potent compounds 7 and 9 having IC 50 values of 1.08 [ 21 ] and 0.99 µM [ 25 ], respectively ( Figure 1 ). Herein, we report the identification and biological evaluation of novel, non-covalent, small molecule SENP1 inhibitors, resulting, to the best of our knowledge, in one of the most potent non-covalent SENP1 inhibitors currently known.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Dual SENP1 and SENP2 Inhibitor

Brand

Bommeli

Rütimann

et al. 2022

IJMS

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SUMOylation is a reversible post–translational modification (PTM) involving covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. Dysregulation of SUMOylation and deSUMOylation results in cellular malfunction and is linked to various diseases, such as cancer. Sentrin-specific proteases (SENPs) were identified for the maturation of SUMOs and the deconjugation of SUMOs from their substrate proteins. Hence, this is a promising target tackling the dysregulation of the SUMOylation process. Herein, we report the discovery of a novel protein-protein interaction (PPI) inhibitor for SENP1-SUMO1 by virtual screening and subsequent medicinal chemistry optimization of the hit molecule. The optimized inhibitor ZHAWOC8697 showed IC50 values of 8.6 μM against SENP1 and 2.3 μM against SENP2. With a photo affinity probe the SENP target was validated. This novel SENP inhibitor represents a new valuable tool for the study of SUMOylation processes and the SENP-associated development of small molecule-based treatment options.

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SUMO1 mediated salubrinal-treated the abnormal remodeling of the subchondral bone in osteoarthritis

Li,

et al. 2023

Preprint

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Background: Osteoarthritis (OA) is the most common joint disorder characterized by cartilage degradation and abnormal subchondral bone remodeling. As a post-translational modification, small ubiquitin-like modifiers (SUMOs) are involved in the pathogenesis of many diseases including arthritis. However, their role in OA remains to be elucidated. Furthermore, although salubrinal is reported to inhibit bone resorption and stimulate bone formation in osteoporosis, its effect on OA is not well understood. Methods: To elucidate the role of salubrinal in OA and any linkage to SUMOylation, 54 mice were employed in 3 randomly assigned groups (n = 18), including the sham control (control), osteoarthritis (OA), and salubrinal-treated OA (OAS). OA was induced by transecting the medial collateral ligament and removing the medial meniscus. Salubrinal was administered subcutaneously at a dose of 2mg/kg daily for 2 weeks. Results: Salubrinal reduced the osteoclast surface and elevated the osteoblast number in the trabecular subchondral bone. It also suppressed osteoclast activities and promoted osteoblast differentiation from bone marrow-derived cells. HE staining and CT imaging revealed that salubrinal improved the microstructure of the subchondral bone, and it reduced OARSI scores and CC/TAC. Silencing SUMO1 attenuated salubrinal’s beneficial effects on osteoclastogenesis and osteoblastogenesis. Conclusions: Salubrinal improved the abnormal remodeling of the subchondral bone in OA, and its beneficial effects were partly mediated by SUMO1.

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Small-molecule inhibitors targeting small ubiquitin-like modifier pathway for the treatment of cancers and other diseases

Cited by 4 publications

References 134 publications

Post-Translational Modifications of STING: A Potential Therapeutic Target

Post-Translational Modifications of STING: A Potential Therapeutic Target

Discovery of a Dual SENP1 and SENP2 Inhibitor

SUMO1 mediated salubrinal-treated the abnormal remodeling of the subchondral bone in osteoarthritis

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