title: Lestaurtinib inhibits histone phosphorylation and androgen-dependent gene expression in prostate cancer cells.
abstract: BACKGROUND
  Epigenetics is defined as heritable changes in gene expression that are not based on changes in the DNA sequence. Posttranslational modification of histone proteins is a major mechanism of epigenetic regulation. The kinase PRK1 (protein kinase C related kinase 1, also known as PKN1) phosphorylates histone H3 at threonine 11 and is involved in the regulation of androgen receptor signalling. Thus, it has been identified as a novel drug target but little is known about PRK1 inhibitors and consequences of its inhibition.
  
  
  RESULTS
  Using a focused library screening approach, we identified the clinical candidate lestaurtinib (also known as CEP-701) as a new inhibitor of PRK1. Based on a generated 3D model of the PRK1 kinase using the homolog PKC-theta (protein kinase c theta) protein as a template, the key interaction of lestaurtinib with PRK1 was analyzed by means of molecular docking studies. Furthermore, the effects on histone H3 threonine phosphorylation and androgen-dependent gene expression was evaluated in prostate cancer cells.
  
  
  CONCLUSIONS
  Lestaurtinib inhibits PRK1 very potently in vitro and in vivo. Applied to cell culture it inhibits histone H3 threonine phosphorylation and androgen-dependent gene expression, a feature that has not been known yet. Thus our findings have implication both for understanding of the clinical activity of lestaurtinib as well as for future PRK1 inhibitors.
authors.affiliation: Albert-Ludwigs-University Freiburg, Institute of Pharmaceutical Sciences, Albertstrasse, Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Köhler
authors.forename: German
authors.initials: G
authors.lastname: Erlenkamp
authors.forename: Adrien
authors.initials: A
authors.lastname: Eberlin
authors.forename: Tobias
authors.initials: T
authors.lastname: Rumpf
authors.forename: Inna
authors.initials: I
authors.lastname: Slynko
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
mesh_terms: D000728:Androgens / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans; D015870:Gene Expression / Q000187:drug effects*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005663:Furans; D006657:Histones; D011944:Receptors, Androgen; C119379:lestaurtinib; C061570:protein kinase N; D011493:Protein Kinase C