Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors
Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the <i>PTPN11</i> gene, which is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been shown to contribute to the progression of va...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3497 |
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| author | Jiajia Dai Yiting Zhang Yanan Gao Xiaoyi Bai Fang Liu Shuo Li Yanyan Yu Wenpeng Hu Ting Shi Dayong Shi Xiangqian Li |
| author_facet | Jiajia Dai Yiting Zhang Yanan Gao Xiaoyi Bai Fang Liu Shuo Li Yanyan Yu Wenpeng Hu Ting Shi Dayong Shi Xiangqian Li |
| author_sort | Jiajia Dai |
| collection | DOAJ |
| description | Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the <i>PTPN11</i> gene, which is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been shown to contribute to the progression of various cancers and is emerging as an important target for anti-tumor drug research. However, past efforts to develop SHP2 inhibitors into drugs have been unsuccessful owing to the positively charged nature of the active site pocket tending to bind negatively charged groups that are usually non-drug-like. Here, a series of uncharged pyrazoline derivatives were designed and developed as new SHP2 inhibitors using a structure-based strategy. Compound <b>4o</b>, which exhibited the strongest SHP2 inhibitory activity, bound directly to the catalytic domain of SHP2 in a competitive manner through multiple hydrogen bonds. Compound <b>4o</b> affected the RAS/MAPK signaling pathway by inhibiting SHP2, and subsequently induced apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. Notably, the oral administration of compound <b>4o</b> in large doses showed no obvious toxicity. In summary, our findings provide a basis for the further development of compound <b>4o</b> as a safe, effective and anti-tumor SHP2 inhibitor. |
| first_indexed | 2024-03-09T11:48:25Z |
| format | Article |
| id | doaj.art-612b57746d114741bae4ecf9451ae822 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:48:25Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-612b57746d114741bae4ecf9451ae8222023-11-30T23:17:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01237349710.3390/ijms23073497Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 InhibitorsJiajia Dai0Yiting Zhang1Yanan Gao2Xiaoyi Bai3Fang Liu4Shuo Li5Yanyan Yu6Wenpeng Hu7Ting Shi8Dayong Shi9Xiangqian Li10State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaCollege of Chemical and Biological Engineering, Shandong University of Science and Technology, Qingdao 266590, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200, ChinaSrc homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the <i>PTPN11</i> gene, which is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been shown to contribute to the progression of various cancers and is emerging as an important target for anti-tumor drug research. However, past efforts to develop SHP2 inhibitors into drugs have been unsuccessful owing to the positively charged nature of the active site pocket tending to bind negatively charged groups that are usually non-drug-like. Here, a series of uncharged pyrazoline derivatives were designed and developed as new SHP2 inhibitors using a structure-based strategy. Compound <b>4o</b>, which exhibited the strongest SHP2 inhibitory activity, bound directly to the catalytic domain of SHP2 in a competitive manner through multiple hydrogen bonds. Compound <b>4o</b> affected the RAS/MAPK signaling pathway by inhibiting SHP2, and subsequently induced apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. Notably, the oral administration of compound <b>4o</b> in large doses showed no obvious toxicity. In summary, our findings provide a basis for the further development of compound <b>4o</b> as a safe, effective and anti-tumor SHP2 inhibitor.https://www.mdpi.com/1422-0067/23/7/3497anti-tumorSHP2inhibitorapoptosistoxicity |
| spellingShingle | Jiajia Dai Yiting Zhang Yanan Gao Xiaoyi Bai Fang Liu Shuo Li Yanyan Yu Wenpeng Hu Ting Shi Dayong Shi Xiangqian Li Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors International Journal of Molecular Sciences anti-tumor SHP2 inhibitor apoptosis toxicity |
| title | Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors |
| title_full | Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors |
| title_fullStr | Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors |
| title_full_unstemmed | Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors |
| title_short | Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors |
| title_sort | toward a treatment of cancer design and in vitro in vivo evaluation of uncharged pyrazoline derivatives as a series of novel shp2 inhibitors |
| topic | anti-tumor SHP2 inhibitor apoptosis toxicity |
| url | https://www.mdpi.com/1422-0067/23/7/3497 |
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