title: Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1).
abstract: The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro.
  
  
  
  We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots.
  
  
  
  The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors. [Formula: see text].
authors: Institute of Organic Chemistry, Albert-Ludwigs-University Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
authors: Dmytro
authors: D
authors: Ostrovskyi
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Tobias
authors: T
authors: Rumpf
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Julia
authors: J
authors: Eib
authors: Institute of Organic Chemistry, Albert-Ludwigs-University Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
authors: Alexandre
authors: A
authors: Lumbroso
authors: Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors: Inna
authors: I
authors: Slynko
authors: Chair of Proteomics & Bioanalytics, Technical University Munich, Emil-Erlenmeyer-Forum 5, 85354 Freising, Germany.|German Cancer Consortium (DKTK), Munich, Germany.|German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Susan
authors: S
authors: Klaeger
authors: Chair of Proteomics & Bioanalytics, Technical University Munich, Emil-Erlenmeyer-Forum 5, 85354 Freising, Germany.|German Cancer Consortium (DKTK), Munich, Germany.|German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Stephanie
authors: S
authors: Heinzlmeir
authors: Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Michael
authors: M
authors: Forster
authors: Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Swiss Federal Institute of Technology (ETH) Zuerich, Vladimir-Prelog-Weg 1-5/10, 8093 Zuerich, Switzerland.
authors: Matthias
authors: M
authors: Gehringer
authors: Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Ellen
authors: E
authors: Pfaffenrot
authors: Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Silke Mona
authors: SM
authors: Bauer
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Karin
authors: K
authors: Schmidtkunz
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.
authors: Sandra
authors: S
authors: Wenzler
authors: Department of Urology, University Freiburg Medical Center, Breisacherstraße 66, 79106 Freiburg im Breisgau, Germany.
authors: Eric
authors: E
authors: Metzger
authors: Chair of Proteomics & Bioanalytics, Technical University Munich, Emil-Erlenmeyer-Forum 5, 85354 Freising, Germany.|German Cancer Consortium (DKTK), Munich, Germany.|German Cancer Research Centre (DKFZ), Heidelberg, Germany.|Bavarian Biomolecular Mass Spectrometry Center, Technical University of Munich, Gregor-Mendel-Straße 4, 85354 Freising, Germany.
authors: Bernhard
authors: B
authors: Kuster
authors: Institute of Pharmacy, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
authors: Stefan
authors: S
authors: Laufer
authors: German Cancer Research Centre (DKFZ), Heidelberg, Germany.|Department of Urology, University Freiburg Medical Center, Breisacherstraße 66, 79106 Freiburg im Breisgau, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors: Roland
authors: R
authors: Schüle
authors: Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany.
authors: Wolfgang
authors: W
authors: Sippl
authors: Institute of Organic Chemistry, Albert-Ludwigs-University Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany.
authors: Bernhard
authors: B
authors: Breit
authors: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg im Breisgau, Germany.|German Cancer Research Centre (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors: Manfred
authors: M
authors: Jung
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; C061570:protein kinase N; D011493:Protein Kinase C
keywords: SAR; epigenetics; histone phosphorylation; kinases; prostate cancer; proteomics; structure–activity relationship studies; tofacitinib