Sumaira Javaid, Seema Zadi, Muhammad Awais, Atia-tul Wahab, Humaira Zafar, Innokentiy Maslennikov and M. Iqbal Choudhary
{"title":"鉴定针对泛素特异性蛋白酶-7 (USP7)的新线索:向潜在的癌症治疗迈出一步†。","authors":"Sumaira Javaid, Seema Zadi, Muhammad Awais, Atia-tul Wahab, Humaira Zafar, Innokentiy Maslennikov and M. Iqbal Choudhary","doi":"10.1039/D4RA06813K","DOIUrl":null,"url":null,"abstract":"<p >Ubiquitin-specific protease-7 (USP7) is an important drug target as it regulates multiple proteins and genes (such as MDM2 and p53) with roles in cancer progression. Its inhibition can hinder the function of oncogenes, increase tumor suppression, and enhance immune response. The current study was designed to express USP7 in a prokaryotic system, followed by screening of small molecules against it using biophysical methods, primarily STD-NMR technique. Among them, 12 compounds showed interaction with USP7 as inferred from NMR-based screening. These compounds further caused destabilization of USP7 by reducing its melting temperature (<em>T</em><small><sub>m</sub></small>) up to 6 °C in thermal shift assay. Molecular docking and simulation studies revealed that these compounds bind to the putative substrate binding pocket of USP7 and thus may block the entry of the substrate. Four compounds <em>i.e.</em>, 4-hydroxy-diphenyl amine (<strong>2</strong>), phenyl-(2,3,4-trihydroxyphenyl) methanone (<strong>3</strong>), 4′-amino-2′,5′-diethoxy benzanilide (<strong>5</strong>), and hydroquinone (<strong>12</strong>), showed anti-cancer activity against colorectal cancerous cells (HCT116) with IC<small><sub>50</sub></small> values in the range of 31–143 μM. These compounds also down-regulated the mRNA expression of the MDM2 gene and up-regulated the mRNA expression of the p53 gene in HCT116 cells, as studied using qPCR analysis. This study thereby identifies several negative modulators of USP7 that can be studied further as potential anti-cancer agents.</p>","PeriodicalId":102,"journal":{"name":"RSC Advances","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/ra/d4ra06813k?page=search","citationCount":"0","resultStr":"{\"title\":\"Identification of new leads against ubiquitin specific protease-7 (USP7): a step towards the potential treatment of cancers†\",\"authors\":\"Sumaira Javaid, Seema Zadi, Muhammad Awais, Atia-tul Wahab, Humaira Zafar, Innokentiy Maslennikov and M. Iqbal Choudhary\",\"doi\":\"10.1039/D4RA06813K\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Ubiquitin-specific protease-7 (USP7) is an important drug target as it regulates multiple proteins and genes (such as MDM2 and p53) with roles in cancer progression. Its inhibition can hinder the function of oncogenes, increase tumor suppression, and enhance immune response. The current study was designed to express USP7 in a prokaryotic system, followed by screening of small molecules against it using biophysical methods, primarily STD-NMR technique. Among them, 12 compounds showed interaction with USP7 as inferred from NMR-based screening. These compounds further caused destabilization of USP7 by reducing its melting temperature (<em>T</em><small><sub>m</sub></small>) up to 6 °C in thermal shift assay. Molecular docking and simulation studies revealed that these compounds bind to the putative substrate binding pocket of USP7 and thus may block the entry of the substrate. Four compounds <em>i.e.</em>, 4-hydroxy-diphenyl amine (<strong>2</strong>), phenyl-(2,3,4-trihydroxyphenyl) methanone (<strong>3</strong>), 4′-amino-2′,5′-diethoxy benzanilide (<strong>5</strong>), and hydroquinone (<strong>12</strong>), showed anti-cancer activity against colorectal cancerous cells (HCT116) with IC<small><sub>50</sub></small> values in the range of 31–143 μM. These compounds also down-regulated the mRNA expression of the MDM2 gene and up-regulated the mRNA expression of the p53 gene in HCT116 cells, as studied using qPCR analysis. 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Identification of new leads against ubiquitin specific protease-7 (USP7): a step towards the potential treatment of cancers†
Ubiquitin-specific protease-7 (USP7) is an important drug target as it regulates multiple proteins and genes (such as MDM2 and p53) with roles in cancer progression. Its inhibition can hinder the function of oncogenes, increase tumor suppression, and enhance immune response. The current study was designed to express USP7 in a prokaryotic system, followed by screening of small molecules against it using biophysical methods, primarily STD-NMR technique. Among them, 12 compounds showed interaction with USP7 as inferred from NMR-based screening. These compounds further caused destabilization of USP7 by reducing its melting temperature (Tm) up to 6 °C in thermal shift assay. Molecular docking and simulation studies revealed that these compounds bind to the putative substrate binding pocket of USP7 and thus may block the entry of the substrate. Four compounds i.e., 4-hydroxy-diphenyl amine (2), phenyl-(2,3,4-trihydroxyphenyl) methanone (3), 4′-amino-2′,5′-diethoxy benzanilide (5), and hydroquinone (12), showed anti-cancer activity against colorectal cancerous cells (HCT116) with IC50 values in the range of 31–143 μM. These compounds also down-regulated the mRNA expression of the MDM2 gene and up-regulated the mRNA expression of the p53 gene in HCT116 cells, as studied using qPCR analysis. This study thereby identifies several negative modulators of USP7 that can be studied further as potential anti-cancer agents.
期刊介绍:
An international, peer-reviewed journal covering all of the chemical sciences, including multidisciplinary and emerging areas. RSC Advances is a gold open access journal allowing researchers free access to research articles, and offering an affordable open access publishing option for authors around the world.