Mengyang Chang, Feng Gao, Jing Chen, Giri Gnawali, Wei Wang
{"title":"MDM2-BCL-XL PROTACs能够降解BCL-XL并稳定p53。","authors":"Mengyang Chang, Feng Gao, Jing Chen, Giri Gnawali, Wei Wang","doi":"10.15212/amm-2022-0022","DOIUrl":null,"url":null,"abstract":"<p><p>Inhibition or degradation of anti-apoptotic protein BCL-X<sub>L</sub> is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-X<sub>L</sub>, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-X<sub>L</sub> PROTACs using MDM2 as E3 ligase for degradation of BCL-X<sub>L</sub>. Three MDM2-BCL-X<sub>L</sub> PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-X<sub>L</sub> inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found <b>BMM4</b> exhibited potent, selective degradation activity against BCL-X<sub>L</sub> and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.</p>","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2022-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10004178/pdf/nihms-1833345.pdf","citationCount":"4","resultStr":"{\"title\":\"MDM2-BCL-X<sub>L</sub> PROTACs enable degradation of BCL-X<sub>L</sub> and stabilization of p53.\",\"authors\":\"Mengyang Chang, Feng Gao, Jing Chen, Giri Gnawali, Wei Wang\",\"doi\":\"10.15212/amm-2022-0022\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Inhibition or degradation of anti-apoptotic protein BCL-X<sub>L</sub> is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-X<sub>L</sub>, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-X<sub>L</sub> PROTACs using MDM2 as E3 ligase for degradation of BCL-X<sub>L</sub>. Three MDM2-BCL-X<sub>L</sub> PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-X<sub>L</sub> inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found <b>BMM4</b> exhibited potent, selective degradation activity against BCL-X<sub>L</sub> and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.</p>\",\"PeriodicalId\":72055,\"journal\":{\"name\":\"Acta materia medica\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-07-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10004178/pdf/nihms-1833345.pdf\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta materia medica\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.15212/amm-2022-0022\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta materia medica","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.15212/amm-2022-0022","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53.
Inhibition or degradation of anti-apoptotic protein BCL-XL is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-XL, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-XL PROTACs using MDM2 as E3 ligase for degradation of BCL-XL. Three MDM2-BCL-XL PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-XL inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found BMM4 exhibited potent, selective degradation activity against BCL-XL and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
