Inhibition of protein kinase C-driven nuclear factor-kappaB activation: synthesis, structure-activity relationship, and pharmacological profiling of pathway specific benzimidazole probe molecules.
A unique series of biologically active chemical probes that selectively inhibit NF-kappaB activation induced by protein kinase C (PKC) pathway activators have been identified through a cell-based phenotypic reporter gene assay. These 2-aminobenzimidazoles represent initial chemical tools to be used in gaining further understanding on the cellular mechanisms driven by B and T cell antigen receptors. Starting from the founding member of this chemical series 1a (notated in PubChem as CID-2858522), we report the chemical synthesis, SAR studies, and pharmacological profiling of this pathway-selective inhibitor of NF-kappaB activation.
Peddibhotla
Satyamaheshwar
S
Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, Florida 32827, USA.
Shi
Ranxin
R
Khan
Pasha
P
Smith
Layton H
LH
Mangravita-Novo
Arianna
A
Vicchiarelli
Michael
M
Su
Ying
Y
Okolotowicz
Karl J
KJ
Cashman
John R
JR
Reed
John C
JC
Roth
Gregory P
GP
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability; D017930:Genes, Reporter; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007376:Interleukin-2 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
C550633:1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(2-((3-hydroxypropyl)amino)-5,6-dimethyl-1H-benzo(d)imidazol-1-yl)ethanone; D001562:Benzimidazoles; D007376:Interleukin-2; D016209:Interleukin-8; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D054852:Small Molecule Libraries; D011493:Protein Kinase C