Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library
Small-molecule protein kinase inhibitors are used for the treatment of cancer, but off-target effects hinder their clinical use. Especially off-target activation of the pregnane X receptor (PXR) has to be considered, as it not only governs drug metabolism and elimination, but also can promote tumor...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/8/1299 |
| _version_ | 1797436376699895808 |
|---|---|
| author | Enni-Kaisa Mustonen Tatu Pantsar Azam Rashidian Juliander Reiner Matthias Schwab Stefan Laufer Oliver Burk |
| author_facet | Enni-Kaisa Mustonen Tatu Pantsar Azam Rashidian Juliander Reiner Matthias Schwab Stefan Laufer Oliver Burk |
| author_sort | Enni-Kaisa Mustonen |
| collection | DOAJ |
| description | Small-molecule protein kinase inhibitors are used for the treatment of cancer, but off-target effects hinder their clinical use. Especially off-target activation of the pregnane X receptor (PXR) has to be considered, as it not only governs drug metabolism and elimination, but also can promote tumor growth and cancer drug resistance. Consequently, PXR antagonism has been proposed for improving cancer drug therapy. Here we aimed to identify small-molecule kinase inhibitors of the Tübingen Kinase Inhibitor Collection (TüKIC) compound library that would act also as PXR antagonists. By a combination of in silico screen and confirmatory cellular reporter gene assays, we identified four novel PXR antagonists and a structurally related agonist with a common phenylaminobenzosuberone scaffold. Further characterization using biochemical ligand binding and cellular protein interaction assays classified the novel compounds as mixed competitive/noncompetitive, passive antagonists, which bind PXR directly and disrupt its interaction with coregulatory proteins. Expression analysis of prototypical PXR target genes ABCB1 and CYP3A4 in LS174T colorectal cancer cells and HepaRG hepatocytes revealed novel antagonists as selective receptor modulators, which showed gene- and tissue-specific effects. These results demonstrate the possibility of dual PXR and protein kinase inhibitors, which might represent added value in cancer therapy. |
| first_indexed | 2024-03-09T11:01:47Z |
| format | Article |
| id | doaj.art-03922f629772424eb174ca323172c458 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T11:01:47Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-03922f629772424eb174ca323172c4582023-12-01T01:13:47ZengMDPI AGCells2073-44092022-04-01118129910.3390/cells11081299Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC LibraryEnni-Kaisa Mustonen0Tatu Pantsar1Azam Rashidian2Juliander Reiner3Matthias Schwab4Stefan Laufer5Oliver Burk6Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, 72074 Tuebingen, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, University of Tuebingen, 72076 Tuebingen, GermanyDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, 72074 Tuebingen, GermanyDepartment of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, University of Tuebingen, 72076 Tuebingen, GermanyDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, 72074 Tuebingen, GermanySmall-molecule protein kinase inhibitors are used for the treatment of cancer, but off-target effects hinder their clinical use. Especially off-target activation of the pregnane X receptor (PXR) has to be considered, as it not only governs drug metabolism and elimination, but also can promote tumor growth and cancer drug resistance. Consequently, PXR antagonism has been proposed for improving cancer drug therapy. Here we aimed to identify small-molecule kinase inhibitors of the Tübingen Kinase Inhibitor Collection (TüKIC) compound library that would act also as PXR antagonists. By a combination of in silico screen and confirmatory cellular reporter gene assays, we identified four novel PXR antagonists and a structurally related agonist with a common phenylaminobenzosuberone scaffold. Further characterization using biochemical ligand binding and cellular protein interaction assays classified the novel compounds as mixed competitive/noncompetitive, passive antagonists, which bind PXR directly and disrupt its interaction with coregulatory proteins. Expression analysis of prototypical PXR target genes ABCB1 and CYP3A4 in LS174T colorectal cancer cells and HepaRG hepatocytes revealed novel antagonists as selective receptor modulators, which showed gene- and tissue-specific effects. These results demonstrate the possibility of dual PXR and protein kinase inhibitors, which might represent added value in cancer therapy.https://www.mdpi.com/2073-4409/11/8/1299pregnane X receptorprotein kinase inhibitorPXR antagonistcancer therapy |
| spellingShingle | Enni-Kaisa Mustonen Tatu Pantsar Azam Rashidian Juliander Reiner Matthias Schwab Stefan Laufer Oliver Burk Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library Cells pregnane X receptor protein kinase inhibitor PXR antagonist cancer therapy |
| title | Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library |
| title_full | Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library |
| title_fullStr | Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library |
| title_full_unstemmed | Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library |
| title_short | Target Hopping from Protein Kinases to PXR: Identification of Small-Molecule Protein Kinase Inhibitors as Selective Modulators of Pregnane X Receptor from TüKIC Library |
| title_sort | target hopping from protein kinases to pxr identification of small molecule protein kinase inhibitors as selective modulators of pregnane x receptor from tukic library |
| topic | pregnane X receptor protein kinase inhibitor PXR antagonist cancer therapy |
| url | https://www.mdpi.com/2073-4409/11/8/1299 |
| work_keys_str_mv | AT ennikaisamustonen targethoppingfromproteinkinasestopxridentificationofsmallmoleculeproteinkinaseinhibitorsasselectivemodulatorsofpregnanexreceptorfromtukiclibrary AT tatupantsar targethoppingfromproteinkinasestopxridentificationofsmallmoleculeproteinkinaseinhibitorsasselectivemodulatorsofpregnanexreceptorfromtukiclibrary AT azamrashidian targethoppingfromproteinkinasestopxridentificationofsmallmoleculeproteinkinaseinhibitorsasselectivemodulatorsofpregnanexreceptorfromtukiclibrary AT julianderreiner targethoppingfromproteinkinasestopxridentificationofsmallmoleculeproteinkinaseinhibitorsasselectivemodulatorsofpregnanexreceptorfromtukiclibrary AT matthiasschwab targethoppingfromproteinkinasestopxridentificationofsmallmoleculeproteinkinaseinhibitorsasselectivemodulatorsofpregnanexreceptorfromtukiclibrary AT stefanlaufer targethoppingfromproteinkinasestopxridentificationofsmallmoleculeproteinkinaseinhibitorsasselectivemodulatorsofpregnanexreceptorfromtukiclibrary AT oliverburk targethoppingfromproteinkinasestopxridentificationofsmallmoleculeproteinkinaseinhibitorsasselectivemodulatorsofpregnanexreceptorfromtukiclibrary |