Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI:10.1021/acsmedchemlett.4c00416

Wenwei Lin, Taosheng Chen

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Abstract

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 (K _d: 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 (K _d: 4.5 ± 0.2 nM), hCDK9/CycT1 (K _d: 5.1 ± 0.6 nM), hMAPK15 (K _d: 340 ± 20 nM), hCASK (K _d: 550 ± 30 nM), and hCAMKK2 (K _d: 530 ± 40 nM). BODIPY FL SNS 032 is therefore a versatile probe for hCAR and multiple kinases.

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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。

人类组成性雄甾烷受体（hCAR）调节异生物代谢。它的配体结合口袋大而灵活，可容纳结构多样的化合物。我们需要一种检测方法来鉴定配体与 hCAR 的结合，但这种方法尚未见报道。在这里，我们首先发现了杂合激酶抑制剂 SNS-032 及其衍生物 THAL-SNS-032 可与 hCAR 结合，然后在 TR-FRET 结合试验中开发了 BODIPY FL SNS 032 (14) 作为高亲和力 hCAR 荧光探针（K d：300 ± 30 nM），并用它来鉴定 hCAR 配体的竞争性结合活性。BODIPY FL SNS 032 还显示出与多种激酶的高结合亲和力，如 hGSK3A（K d：4.5 ± 0.2 nM）、hCDK9/CycT1（K d：5.1 ± 0.6 nM）、hMAPK15（K d：340 ± 20 nM）、hCASK（K d：550 ± 30 nM）和 hCAMKK2（K d：530 ± 40 nM）。因此，BODIPY FL SNS 032 是检测 hCAR 和多种激酶的多功能探针。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： 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: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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