Design, synthesis, and biological evaluation of benzodiazepine-based SUMO-specific protease 1 inhibitors

Qiao, Zhitao; Wang, Weiwei; Wang, Lie; Wen, Donghua; Zhao, Yulan; Wang, Qing; Meng, Qingqing; Chen, Guoqiang; Wu, Yingli; Zhou, Huchen

doi:10.1016/j.bmcl.2011.08.101

Cited by 43 publications

(31 citation statements)

References 18 publications

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“…If so, inhibiting the inflammatory aspects of beige precursors with NF-kB inhibitor can protect obesity people from diabetes phenotype. [34][35][36] In summary, our studies have defined the role of the SENP1-mediated protein SUMOylation in pancreatic immune responses, b-cell damages and consequently diabetes progression. Our studies provide therapeutic approaches by delivery of NEMO inhibitory peptides or NF-kB inhibitors for treatment of type 1 diabetes.…”

Section: Nf-kb Inhibitor To Treat Diabetesmentioning

confidence: 88%

The role of adipose-derived inflammatory cytokines in type 1 diabetes

et al. 2016

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Adipose tissue dysfunction correlates with the development of diabetes. Mice with an adipocyte-specific deletion of the SUMO-specific protease SENP1 develop symptoms of type-1 diabetes mellitus (T1DM). Peri-pancreatic adipocytes (PATs) exert both systemic and paracrine effects on pancreases function. Our recent studies report that PATs of SENP1-deficient mice have increased proinflammatory cytokine production compared with other adipose depots. Proinflammatory cytokines produced from PATs not only have direct cytotoxic effects on pancreatic islets, but also increase CCL5 expression in adjacent pancreatic islets, which induces persistent inflammation in pancreases by acquisition of Th1 and Th17 effector T cell subsets. Small ubiquitin-like modifier (SUMO) can post-translationally conjugate to cellular proteins (SUMOylation) and modulate their biological functions. Several components in SUMOylation associate with T1DM susceptibility. We find that SUMOylation of NF-κB essential molecule NEMO augments NF-κB activity, NF-κB-dependent cytokine production and pancreatic inflammation. NF-κB inhibitor should provide therapeutic approach to block PAT inflammation and ameliorate the T1DM phenotype. We further propose that adipocytes in PATs may play a primary role in establishing pancreatic immune regulation at onset of diabetes, providing new insights into the molecular pathogenesis of type 1 diabetes.

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Section: Nf-kb Inhibitor To Treat Diabetesmentioning

confidence: 88%

The role of adipose-derived inflammatory cytokines in type 1 diabetes

et al. 2016

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“…Furthermore, SENP1 has also been revealed to be involved in the development and progression of several types of cancer (12,13). However, while SENP1-specific inhibitors have been designed (14,15), whether SENP1 is a potential drug target for cancer treatment remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of SENP1 induces radiosensitization in lung cancer cells

Wang

Zhi

Zhang

et al. 2013

Experimental and Therapeutic Medicine

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Lung cancer is one of the most common and lethal types of malignancy. To date, radiotherapy and chemotherapy have been used as the two major treatment methods. However, radioresistance of lung cancer remains a therapeutic hindrance. The aim of this study was to identify whether small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) is a marker of radioresistance that may serve as a target for enhancing the efficacy of lung carcinoma radiotherapy. SENP1 was observed to be overexpressed in lung cancer tissues, and the modulation of SENP1 expression was demonstrated to significantly affect the proliferation of lung cancer cells. Moreover, silencing the expression of SENP1 using small interfering RNA (siRNA) significantly sensitized lung cancer cells to radiation. Mechanically, it was demonstrated that SENP1 depletion significantly enhanced ionizing radiation (IR)-induced cell cycle arrest, γ-H2AX expression and apoptosis. Thus, these data suggest that SENP1 may be a desirable drug target for lung carcinoma radiotherapy.

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“…The first report of a successful design of SENP1 inhibitors came only recently, and involves a series of SENP1 inhibitors based on a benzodiazepine scaffold which showed inhibitory activity as high as IC50 = 9.2 μM. The compounds with the best SENP1 inhibitory activity were tested against PCa cells (PC-3) to evaluate their ability to inhibit cancer cell growth in vitro , with IC50 values as low as 13.0 μM detected [65]. Hopefully, progression of a selective inhibitor of either SENP1 or SENP3 to in vivo testing as well as in the setting of a dedicated clinical trial might lead to an effective therapeutic approach to restoring balance to the aberrant SUMO pathway of PCa patients.…”

Section: Discussionmentioning

confidence: 99%

The Role of the Small Ubiquitin-Related Modifier (SUMO) Pathway in Prostate Cancer

Vlachostergios

Papandreou

2012

Biomolecules

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SUMO (small ubiquitin-related modifier) conjugation is a reversible three-step process of protein post-translational modifications mediating protein-protein interactions, subcellular compartmentalization and regulation of transcriptional events. Among divergent transcription factors regulated by SUMOylation and deSUMOylation, the androgen receptor (AR) is of exceptional significance, given its established role in prostate carcinogenesis. The enzymes of the SUMO pathway can have diverse effects on AR transcriptional activity, either via direct modification of the AR or through modification of AR co-regulators. Accumulating in vitro and in vivo evidence implicates the SUMO pathway in AR-dependent signaling. Prostate cancer cell proliferation and hypoxia-induced angiogenesis are also regulated by the SUMO pathway, through an AR-independent mechanism. Thus, an important role has been revealed for members of the SUMO pathway in prostate cancer (PCa) development and progression, offering new therapeutic targets.

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Design, synthesis, and biological evaluation of benzodiazepine-based SUMO-specific protease 1 inhibitors

Cited by 43 publications

References 18 publications

The role of adipose-derived inflammatory cytokines in type 1 diabetes

The role of adipose-derived inflammatory cytokines in type 1 diabetes

Inhibition of SENP1 induces radiosensitization in lung cancer cells

The Role of the Small Ubiquitin-Related Modifier (SUMO) Pathway in Prostate Cancer

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