{"title":"将 BODIPY FL SNS 032 开发为一种多功能探针，用于检测组成型雄甾烷受体和多种激酶","authors":"Wenwei Lin, and , Taosheng Chen*, ","doi":"10.1021/acsmedchemlett.4c0041610.1021/acsmedchemlett.4c00416","DOIUrl":null,"url":null,"abstract":"<p >Human constitutive androstane receptor (hCAR) regulates xenobiotic metabolism. Its large and flexible ligand binding pocket can accommodate structurally diverse compounds. An assay for characterizing the binding of ligands to hCAR is needed but has not been reported. Here, we first discovered the promiscuous kinase inhibitor SNS-032 and its derivative THAL-SNS-032 as binders of hCAR, then developed BODIPY FL SNS 032 (<b>14</b>) as a high-affinity hCAR fluorescent probe (<i>K</i><sub>d</sub>: 300 ± 30 nM) in a TR-FRET binding assay and used it to characterize hCAR ligands for their competitive binding activities. BODIPY FL SNS 032 also displayed high binding affinities to multiple kinases, such as hGSK3A (<i>K</i><sub>d</sub>: 4.5 ± 0.2 nM), hCDK9/CycT1 (<i>K</i><sub>d</sub>: 5.1 ± 0.6 nM), hMAPK15 (<i>K</i><sub>d</sub>: 340 ± 20 nM), hCASK (<i>K</i><sub>d</sub>: 550 ± 30 nM), and hCAMKK2 (<i>K</i><sub>d</sub>: 530 ± 40 nM). BODIPY FL SNS 032 is therefore a versatile probe for hCAR and multiple kinases.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1987–1996 1987–1996"},"PeriodicalIF":3.5000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases\",\"authors\":\"Wenwei Lin, and , Taosheng Chen*, \",\"doi\":\"10.1021/acsmedchemlett.4c0041610.1021/acsmedchemlett.4c00416\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Human constitutive androstane receptor (hCAR) regulates xenobiotic metabolism. Its large and flexible ligand binding pocket can accommodate structurally diverse compounds. An assay for characterizing the binding of ligands to hCAR is needed but has not been reported. Here, we first discovered the promiscuous kinase inhibitor SNS-032 and its derivative THAL-SNS-032 as binders of hCAR, then developed BODIPY FL SNS 032 (<b>14</b>) as a high-affinity hCAR fluorescent probe (<i>K</i><sub>d</sub>: 300 ± 30 nM) in a TR-FRET binding assay and used it to characterize hCAR ligands for their competitive binding activities. BODIPY FL SNS 032 also displayed high binding affinities to multiple kinases, such as hGSK3A (<i>K</i><sub>d</sub>: 4.5 ± 0.2 nM), hCDK9/CycT1 (<i>K</i><sub>d</sub>: 5.1 ± 0.6 nM), hMAPK15 (<i>K</i><sub>d</sub>: 340 ± 20 nM), hCASK (<i>K</i><sub>d</sub>: 550 ± 30 nM), and hCAMKK2 (<i>K</i><sub>d</sub>: 530 ± 40 nM). BODIPY FL SNS 032 is therefore a versatile probe for hCAR and multiple kinases.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":\"15 11\",\"pages\":\"1987–1996 1987–1996\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-10-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00416\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00416","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases
Human constitutive androstane receptor (hCAR) regulates xenobiotic metabolism. Its large and flexible ligand binding pocket can accommodate structurally diverse compounds. An assay for characterizing the binding of ligands to hCAR is needed but has not been reported. Here, we first discovered the promiscuous kinase inhibitor SNS-032 and its derivative THAL-SNS-032 as binders of hCAR, then developed BODIPY FL SNS 032 (14) as a high-affinity hCAR fluorescent probe (Kd: 300 ± 30 nM) in a TR-FRET binding assay and used it to characterize hCAR ligands for their competitive binding activities. BODIPY FL SNS 032 also displayed high binding affinities to multiple kinases, such as hGSK3A (Kd: 4.5 ± 0.2 nM), hCDK9/CycT1 (Kd: 5.1 ± 0.6 nM), hMAPK15 (Kd: 340 ± 20 nM), hCASK (Kd: 550 ± 30 nM), and hCAMKK2 (Kd: 530 ± 40 nM). BODIPY FL SNS 032 is therefore a versatile probe for hCAR and multiple kinases.
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ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
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