2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives, a novel class of SENP1 inhibitors: Virtual screening, synthesis and biological evaluation

Chen, Yingyi; Wen, Donghua; Huang, Zhimin; Huang, Min; Luo, Yu; Liu, Bin; Han, Lu; Wu, Yingli; Peng, Yunfeng; Zhang, Jian

doi:10.1016/j.bmcl.2012.09.037

Cited by 40 publications

(39 citation statements)

References 18 publications

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“…In human PCa cells, SENP1 controls critical mediators of PCa formation and progression specifically the androgen receptor, hypoxia-inducible factor 1a (HIF1α), c-jun, and cyclin D1 [3, 5–7]. These observations caused the recent drive to develop SENP1-selective inhibitors [8, 9]. However, engineered mice with selective expression of the SENP1 transgene in the epithelia of the prostate gland (PG) do not develop cancer [2].…”

Section: Introductionmentioning

confidence: 99%

SENP1 regulates PTEN stability to dictate prostate cancer development

et al. 2016

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SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptor-dependent and -independent cell proliferation, stabilizes HIF1a, increases VEGF, and supports angiogenesis. However, mice expressing an androgen-responsive promoter driven SENP1-transgene (SENP1-Tg) develop high-grade prostatic intraepithelial neoplasia, but not carcinoma. We now show that tumor suppressive PTEN signaling is induced in SENP1-Tg to enhance prostate epithelial cell apoptosis. SENP1 blocks SUMO1-dependent ubiquitylation and degradation of PTEN. In the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol, where binding to ubiquitin-E3 ligase WWP2 occurs. Concurrently, WWP2 is also SUMOylated, which potentiates its interaction with PTEN. Thus, SENP1 directs ubiquitin-E3-substrate association to control PTEN stability. PTEN serves as a barrier for SENP1-mediated prostate carcinogenesis as SENP1-Tg mice develop invasive carcinomas only after PTEN reduction. Hence, SENP1 modulates multiple facets of carcinogenesis and may serve as a target specifically for aggressive PTEN-deficient PCa.

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Section: Introductionmentioning

confidence: 99%

SENP1 regulates PTEN stability to dictate prostate cancer development

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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“…Here, the strongest of these inhibitors was the reported compound 1 (8e from Chen et al .) . It was disclosed with an IC 50 of 1.08 μM and displayed a value of 38 μM (buffer with BSA) and 2.6 μM (buffer with CHAPS) in our fluorogenic bioassays.…”

Section: Figurementioning

confidence: 80%

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

et al. 2020

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Sentrin-specific proteases (SENPs) are responsible for the maturation of small ubiquitin-like modifiers (SUMOs) and the deconjugation of SUMOs from their substrate proteins. Studies on prostate cancer revealed an overexpression of SENP1, which promotes prostate cancer progression as well as metastasis. Therefore, SENP1 has been identified as a novel drug target against prostate cancer. Herein, we report the discovery and biological evaluation of potent and selective SENP1 inhibitors. A structure-activity relationship (SAR) of the newly identified pyridone scaffold revealed allosteric inhibitors with very attractive in vitro ADMET properties regarding plasma binding and plasma stability for this challenging target. This study also emphasizes the importance of biochemical mode of inhibition studies for de novo designed inhibitors.

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2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives, a novel class of SENP1 inhibitors: Virtual screening, synthesis and biological evaluation

Cited by 40 publications

References 18 publications

SENP1 regulates PTEN stability to dictate prostate cancer development

SENP1 regulates PTEN stability to dictate prostate cancer development

Inhibition of SENP1 induces radiosensitization in lung cancer cells

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

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