Chemical biology strategy reveals pathway-selective inhibitor of NF-kappaB activation induced by protein kinase C.
Dysregulation of NF-kappaB activity contributes to many autoimmune and inflammatory diseases. At least nine pathways for NF-kappaB activation have been identified, most of which converge on the IkappaB kinases (IKKs). Although IKKs represent logical targets for potential drug discovery, chemical inhibitors of IKKs suppress all known NF-kappaB activation pathways and thus lack the selectivity required for safe use. A unique NF-kappaB activation pathway is initiated by protein kinase C (PKC) that is stimulated by antigen receptors and many growth factor receptors. Using a cell-based high-throughput screening (HTS) assay and chemical biology strategy, we identified a 2-aminobenzimidazole compound, CID-2858522, which selectively inhibits the NF-kappaB pathway induced by PKC, operating downstream of PKC but upstream of IKKbeta, without inhibiting other NF-kappaB activation pathways. In human B cells stimulated through surface immunoglobulin, CID-2858522 inhibited NF-kappaB DNA-binding activity and expression of endogenous NF-kappaB-dependent target gene, TRAF1. Altogether, as a selective chemical inhibitor of the NF-kappaB pathway induced by PKC, CID-2858522 serves as a powerful research tool and may reveal new paths toward therapeutically useful NF-kappaB inhibitors.
Sanford-Burnham Medical Research Institute, La Jolla, San Diego, California 92037, USA.
Ranxin
R
Shi
Daniel
D
Re
Eric
E
Dudl
Michael
M
Cuddy
Karl J
KJ
Okolotowicz
Russell
R
Dahl
Ying
Y
Su
Andrew
A
Hurder
Shinichi
S
Kitada
Satyamaheshwar
S
Peddibhotla
Gregory P
GP
Roth
Layton H
LH
Smith
Thomas J
TJ
Kipps
Nicholas
N
Cosford
John
J
Cashman
John C
JC
Reed
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007075:Immunoglobulin M / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D019169:Jurkat Cells; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
D001562:Benzimidazoles; D007075:Immunoglobulin M; D007376:Interleukin-2; D016328:NF-kappa B; D054852:Small Molecule Libraries; C027391:2-aminobenzimidazole; D051550:I-kappa B Kinase; D011493:Protein Kinase C