@PhdThesis{diss_mods_00019480,
  author = 	{Halekotte, Jakob Zacharias},
  title = 	{Design, Synthesis, and Optimization of CK1$\delta$ Inhibitors},
  year = 	{2016},
  publisher = 	{Christian-Albrechts-Universit{\"a}t zu Kiel},
  address = 	{Kiel},
  keywords = 	{Kinase Inhibitors; CK1; Protein Kinase; Kinaseinhibitoren; Proteinkinase},
  abstract = 	{Protein Kinase CK1$\delta$ is an important determinant in development and progression of severe pathogenic disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer. Consequently, potent and selevctive small molecule kinase inhibitors have been pursued with increasing interest over the past decade. However, the existence of further five evolutionary conserved human CK1 isoforms that possess similar, different, or even opposite physiological and pathophysiological implications renders the design of suitable candidates enormously comlicated. Especially highly related CK1 isoforms $\delta$ and $\epsilon$ remain difficult to discriminate and have therefore often been reported as redundant, rather by means of missing evidence. The present study reports on in silico design, synthesis, and biological evaluation of novel and optimized 4,5-diaryl-imidazoles as potent dual-specific ATP-competitive inhibitors of CK1 isoforms $\delta$ and $\epsilon$ as well as p38$\alpha$ mitogen-activated protein kinase. In fact, most promising candidate is among the most effective CK1 inhibitors published to date with an IC50 value in the low single-digit nanomolar range and good selectivity in a panel of 321 protein kinases. Consequently, it holds the potential to serve as an important biological tool for pharmacological evaluation of CK1-dependent activity such as in stem cell applications.},
  url = 	{https://macau.uni-kiel.de/receive/diss_mods_00019480},
  file = 	{:https://macau.uni-kiel.de/servlets/MCRFileNodeServlet/dissertation_derivate_00006751/Dissertation_Jakob_Halekotte.pdf:PDF},
  language = 	{en}
}