Discovering monoacylglycerol lipase inhibitors by a combination of fluorogenic substrate assay and activity-based protein profiling
The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment...
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| Published in | Frontiers in pharmacology Vol. 13; p. 941522 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
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29.08.2022
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| Abstract | The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment of diseases such as neurodegenerative disease and inflammation, pain, as well as cancer. Despite a number of MAGL inhibitors been reported, inhibitors with new chemotypes are still required. Here, we developed a substrate-based fluorescence assay by using a new fluorogenic probe
and successfully screened a focused library containing 320 natural organic compounds. Furthermore, we applied activity-based protein profiling (ABPP) as an orthogonal method to confirm the inhibitory activity against MAGL in the primary substrate-based screening. Our investigations culminated in the identification of two major compound classes, including quinoid diterpene (
, cryptotanshinone) and
-carbolines (
and
, cis- and trans-isomers), with significant potency towards MAGL and good selectivity over other 2-AG hydrolases (ABHD6 and ABHD12). Moreover, these compounds also showed antiproliferative activities against multiple cancer cells, including A431, H1975, B16-F10, OVCAR-3, and A549. Remarkably,
achieved complete inhibition towards endogenous MAGL in most cancer cells determined by ABPP. Our results demonstrate the potential utility of the substrate-based fluorescence assay in combination with ABPP for rapidly discovering MAGL inhibitors, as well as providing an effective approach to identify potential targets for compounds with significant biological activities. |
|---|---|
| AbstractList | The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment of diseases such as neurodegenerative disease and inflammation, pain, as well as cancer. Despite a number of MAGL inhibitors been reported, inhibitors with new chemotypes are still required. Here, we developed a substrate-based fluorescence assay by using a new fluorogenic probe
and successfully screened a focused library containing 320 natural organic compounds. Furthermore, we applied activity-based protein profiling (ABPP) as an orthogonal method to confirm the inhibitory activity against MAGL in the primary substrate-based screening. Our investigations culminated in the identification of two major compound classes, including quinoid diterpene (
, cryptotanshinone) and
-carbolines (
and
, cis- and trans-isomers), with significant potency towards MAGL and good selectivity over other 2-AG hydrolases (ABHD6 and ABHD12). Moreover, these compounds also showed antiproliferative activities against multiple cancer cells, including A431, H1975, B16-F10, OVCAR-3, and A549. Remarkably,
achieved complete inhibition towards endogenous MAGL in most cancer cells determined by ABPP. Our results demonstrate the potential utility of the substrate-based fluorescence assay in combination with ABPP for rapidly discovering MAGL inhibitors, as well as providing an effective approach to identify potential targets for compounds with significant biological activities. The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment of diseases such as neurodegenerative disease and inflammation, pain, as well as cancer. Despite a number of MAGL inhibitors been reported, inhibitors with new chemotypes are still required. Here, we developed a substrate-based fluorescence assay by using a new fluorogenic probe AA-HNA and successfully screened a focused library containing 320 natural organic compounds. Furthermore, we applied activity-based protein profiling (ABPP) as an orthogonal method to confirm the inhibitory activity against MAGL in the primary substrate-based screening. Our investigations culminated in the identification of two major compound classes, including quinoid diterpene (23, cryptotanshinone) and β-carbolines (82 and 93, cis- and trans-isomers), with significant potency towards MAGL and good selectivity over other 2-AG hydrolases (ABHD6 and ABHD12). Moreover, these compounds also showed antiproliferative activities against multiple cancer cells, including A431, H1975, B16-F10, OVCAR-3, and A549. Remarkably, 23 achieved complete inhibition towards endogenous MAGL in most cancer cells determined by ABPP. Our results demonstrate the potential utility of the substrate-based fluorescence assay in combination with ABPP for rapidly discovering MAGL inhibitors, as well as providing an effective approach to identify potential targets for compounds with significant biological activities. The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment of diseases such as neurodegenerative disease and inflammation, pain, as well as cancer. Despite a number of MAGL inhibitors been reported, inhibitors with new chemotypes are still required. Here, we developed a substrate-based fluorescence assay by using a new fluorogenic probe AA-HNA and successfully screened a focused library containing 320 natural organic compounds. Furthermore, we applied activity-based protein profiling (ABPP) as an orthogonal method to confirm the inhibitory activity against MAGL in the primary substrate-based screening. Our investigations culminated in the identification of two major compound classes, including quinoid diterpene (23, cryptotanshinone) and β-carbolines (82 and 93, cis- and trans-isomers), with significant potency towards MAGL and good selectivity over other 2-AG hydrolases (ABHD6 and ABHD12). Moreover, these compounds also showed antiproliferative activities against multiple cancer cells, including A431, H1975, B16-F10, OVCAR-3, and A549. Remarkably, 23 achieved complete inhibition towards endogenous MAGL in most cancer cells determined by ABPP. Our results demonstrate the potential utility of the substrate-based fluorescence assay in combination with ABPP for rapidly discovering MAGL inhibitors, as well as providing an effective approach to identify potential targets for compounds with significant biological activities.The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment of diseases such as neurodegenerative disease and inflammation, pain, as well as cancer. Despite a number of MAGL inhibitors been reported, inhibitors with new chemotypes are still required. Here, we developed a substrate-based fluorescence assay by using a new fluorogenic probe AA-HNA and successfully screened a focused library containing 320 natural organic compounds. Furthermore, we applied activity-based protein profiling (ABPP) as an orthogonal method to confirm the inhibitory activity against MAGL in the primary substrate-based screening. Our investigations culminated in the identification of two major compound classes, including quinoid diterpene (23, cryptotanshinone) and β-carbolines (82 and 93, cis- and trans-isomers), with significant potency towards MAGL and good selectivity over other 2-AG hydrolases (ABHD6 and ABHD12). Moreover, these compounds also showed antiproliferative activities against multiple cancer cells, including A431, H1975, B16-F10, OVCAR-3, and A549. Remarkably, 23 achieved complete inhibition towards endogenous MAGL in most cancer cells determined by ABPP. Our results demonstrate the potential utility of the substrate-based fluorescence assay in combination with ABPP for rapidly discovering MAGL inhibitors, as well as providing an effective approach to identify potential targets for compounds with significant biological activities. The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly metabolized by monoacylglycerol lipase (MAGL) in the brain. Selective inhibitors of MAGL provide valuable insights into the role of 2-AG in a variety of (patho)physiological processes and are potential therapeutics for the treatment of diseases such as neurodegenerative disease and inflammation, pain, as well as cancer. Despite a number of MAGL inhibitors been reported, inhibitors with new chemotypes are still required. Here, we developed a substrate-based fluorescence assay by using a new fluorogenic probe AA-HNA and successfully screened a focused library containing 320 natural organic compounds. Furthermore, we applied activity-based protein profiling (ABPP) as an orthogonal method to confirm the inhibitory activity against MAGL in the primary substrate-based screening. Our investigations culminated in the identification of two major compound classes, including quinoid diterpene ( 23 , cryptotanshinone) and β -carbolines ( 82 and 93 , cis- and trans-isomers), with significant potency towards MAGL and good selectivity over other 2-AG hydrolases (ABHD6 and ABHD12). Moreover, these compounds also showed antiproliferative activities against multiple cancer cells, including A431, H1975, B16-F10, OVCAR-3, and A549. Remarkably, 23 achieved complete inhibition towards endogenous MAGL in most cancer cells determined by ABPP. Our results demonstrate the potential utility of the substrate-based fluorescence assay in combination with ABPP for rapidly discovering MAGL inhibitors, as well as providing an effective approach to identify potential targets for compounds with significant biological activities. |
| Author | Yang, Na Zhang, Qianwen Yang, Kai Jiang, Jianbing Lei, Qian Yu, Zhiyi Deng, Hui |
| AuthorAffiliation | 5 Health Science Center , School of Pharmaceutical Sciences , Shenzhen University , Shenzhen , Guangdong , China 1 Department of Respiratory and Critical Care Medicine , West China Hospital , Sichuan University , Chengdu , Sichuan , China 4 Department of Medicinal Chemistry , School of Pharmaceutical Sciences , Cheeloo College of Medicine , Shandong University , Jinan , Shandong , China 2 Targeted Tracer Research and Development Laboratory , Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center , West China Hospital , Sichuan University , Chengdu , Sichuan , China 3 Department of Obstetrics and Gynecology , West China Second University Hospital , Sichuan University , Chengdu , Sichuan , China |
| AuthorAffiliation_xml | – name: 4 Department of Medicinal Chemistry , School of Pharmaceutical Sciences , Cheeloo College of Medicine , Shandong University , Jinan , Shandong , China – name: 1 Department of Respiratory and Critical Care Medicine , West China Hospital , Sichuan University , Chengdu , Sichuan , China – name: 2 Targeted Tracer Research and Development Laboratory , Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center , West China Hospital , Sichuan University , Chengdu , Sichuan , China – name: 5 Health Science Center , School of Pharmaceutical Sciences , Shenzhen University , Shenzhen , Guangdong , China – name: 3 Department of Obstetrics and Gynecology , West China Second University Hospital , Sichuan University , Chengdu , Sichuan , China |
| Author_xml | – sequence: 1 givenname: Hui surname: Deng fullname: Deng, Hui organization: Targeted Tracer Research and Development Laboratory, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China – sequence: 2 givenname: Qianwen surname: Zhang fullname: Zhang, Qianwen organization: Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China – sequence: 3 givenname: Qian surname: Lei fullname: Lei, Qian organization: Targeted Tracer Research and Development Laboratory, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China – sequence: 4 givenname: Na surname: Yang fullname: Yang, Na organization: Targeted Tracer Research and Development Laboratory, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China – sequence: 5 givenname: Kai surname: Yang fullname: Yang, Kai organization: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China – sequence: 6 givenname: Jianbing surname: Jiang fullname: Jiang, Jianbing organization: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China – sequence: 7 givenname: Zhiyi surname: Yu fullname: Yu, Zhiyi organization: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/36105202$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1038/nn.2720 10.1038/nchembio.129 10.1038/nn.2616 10.1016/j.tips.2019.02.002 10.1146/annurev.biochem.75.101304.124125 10.1021/ci200227u 10.1016/j.chembiol.2013.01.012 10.1111/j.1748-1716.2011.02280.x 10.2174/1872213X13666190816160240 10.1016/j.canlet.2011.03.007 10.1002/jcc.21334 10.1016/j.fitote.2020.104633 10.1073/pnas.1314017110 10.1073/pnas.061029898 10.1016/j.chembiol.2007.11.006 10.1021/jm800978m 10.1210/er.2005-0009 10.1016/j.plefa.2015.11.006 10.1016/j.cell.2009.11.027 10.1111/bph.12298 10.1016/j.plipres.2016.02.002 10.1002/ptr.6647 10.1038/365061a0 10.1016/j.celrep.2012.09.030 10.1111/bph.12411 10.1074/jbc.M110.215434 10.1126/science.1209200 10.3389/fendo.2015.00086 10.1016/j.sajb.2020.10.022 10.1002/cam4.1691 10.1021/acs.analchem.9b05826 10.3390/ijms20061305 10.1016/j.ejmech.2020.112353 10.1126/science.1470919 10.1016/j.scib.2022.01.014 10.1021/acs.jmedchem.8b01958 10.4103/jcrt.JCRT_488_18 10.1016/j.apsb.2019.10.006 10.1016/j.lfs.2012.10.025 10.1111/febs.12260 10.3164/jcbn.08-230 10.2174/1389450117666160112113703 |
| ContentType | Journal Article |
| Copyright | Copyright © 2022 Deng, Zhang, Lei, Yang, Yang, Jiang and Yu. Copyright © 2022 Deng, Zhang, Lei, Yang, Yang, Jiang and Yu. 2022 Deng, Zhang, Lei, Yang, Yang, Jiang and Yu |
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| Keywords | fluorogenic substrate assay monoacylglycerol lipase activity-based protein profiling anticancer activity inhibitor discovery |
| Language | English |
| License | Copyright © 2022 Deng, Zhang, Lei, Yang, Yang, Jiang and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Yulin Tian, Chinese Academy of Medical Sciences and Peking Union Medical College, China These authors contributed equally to this work and share first authorship Edited by: André Luiz Lourenço, University of California, San Francisco, United States This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology Xiao-Peng He, East China University of Science and Technology, China |
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| Title | Discovering monoacylglycerol lipase inhibitors by a combination of fluorogenic substrate assay and activity-based protein profiling |
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