产品号 #72712_C
90 kDa ribosomal S6 kinase (RSK) inhibitor
概述
BI-D1870 inhibits the 90 kDa ribosomal S6 kinases (RSKs), which are serine/threonine kinases involved in diverse cellular processes including growth, survival, and motility (Romeo et al.).
MAINTENANCE AND SELF-RENEWAL
· Reduces neural stem cell proliferation and self-renewal in vitro (Karelina et al.).
CANCER RESEARCH
· Inhibits growth of breast cancer cell lines (Stratford et al., Dhillon et al.).
Alternative Names
Not applicable
Cell Type
Cancer Cells and Cell Lines, Mammary Cells, Neural Stem and Progenitor Cells
Species
Human, Mouse, Non-Human Primate, Other, Rat
Area of Interest
Cancer, Epithelial Cell Biology, Stem Cell Biology
CAS Number
501437-28-1
Chemical Formula
C₁₉H₂₃F₂N₅O₂
Molecular Weight
391.4 g/mol
Purity
≥ 95%
Target
RSK
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (1)
Publications (5)
Ribosomal S6 kinase regulates ischemia-induced progenitor cell proliferation in the adult mouse hippocampus. Experimental neurology 2014 MAR
Abstract
Ischemia-induced progenitor cell proliferation is a prominent example of the adult mammalian brain's ability to regenerate injured tissue resulting from pathophysiological processes. In order to better understand and exploit the cell signaling mechanisms that regulate ischemia-induced proliferation, we examined the role of the p42/44 mitogen-activated protein kinase (MAPK) cascade effector ribosomal S6 kinase (RSK) in this process. Here, using the endothelin-1 ischemia model in wild type mice, we show that the activated form of RSK is expressed in the progenitor cells of the subgranular zone (SGZ) after intrahippocampal cerebral ischemia. Further, RSK inhibition significantly reduces ischemia-induced SGZ progenitor cell proliferation. Using the neurosphere assay, we also show that both SGZ- and subventricular zone (SVZ)-derived adult neural stem cells (NSC) exhibit a significant reduction in proliferation in the presence of RSK and MAPK inhibitors. Taken together, these data reveal RSK as a regulator of ischemia-induced progenitor cell proliferation, and as such, suggest potential therapeutic value may be gained by specifically targeting the regulation of RSK in the progenitor cell population of the SGZ.
Targeting p90 ribosomal S6 kinase eliminates tumor-initiating cells by inactivating Y-box binding protein-1 in triple-negative breast cancers. Stem cells (Dayton, Ohio) 2012 JUL
Abstract
Y-box binding protein-1 (YB-1) is the first reported oncogenic transcription factor to induce the tumor-initiating cell (TIC) surface marker CD44 in triple-negative breast cancer (TNBC) cells. In order for CD44 to be induced, YB-1 must be phosphorylated at S102 by p90 ribosomal S6 kinase (RSK). We therefore questioned whether RSK might be a tractable molecular target to eliminate TICs. In support of this idea, injection of MDA-MB-231 cells expressing Flag-YB-1 into mice increased tumor growth as well as enhanced CD44 expression. Despite enrichment for TICs, these cells were sensitive to RSK inhibition when treated ex vivo with BI-D1870. Targeting RSK2 with small interfering RNA (siRNA) or small molecule RSK kinase inhibitors (SL0101 and BI-D1870) blocked TNBC monolayer cell growth by ∼100%. In a diverse panel of breast tumor cell line models RSK2 siRNA predominantly targeted models of TNBC. RSK2 inhibition decreased CD44 promoter activity, CD44 mRNA, protein expression, and mammosphere formation. CD44(+) cells had higher P-RSK(S221/227) , P-YB-1(S102) , and mitotic activity relative to CD44(-) cells. Importantly, RSK2 inhibition specifically suppressed the growth of TICs and triggered cell death. Moreover, silencing RSK2 delayed tumor initiation in mice. In patients, RSK2 mRNA was associated with poor disease-free survival in a cohort of 244 women with breast cancer that had not received adjuvant treatment, and its expression was highest in the basal-like breast cancer subtype. Taking this further, we report that P-RSK(S221/227) is present in primary TNBCs and correlates with P-YB-1(S102) as well as CD44. In conclusion, RSK2 inhibition provides a novel therapeutic avenue for TNBC and holds the promise of eliminating TICs.
Regulation and function of the RSK family of protein kinases. The Biochemical journal 2012 JAN
Abstract
The RSK (90 kDa ribosomal S6 kinase) family comprises a group of highly related serine/threonine kinases that regulate diverse cellular processes, including cell growth, proliferation, survival and motility. This family includes four vertebrate isoforms (RSK1, RSK2, RSK3 and RSK4), and single family member orthologues are also present in Drosophila and Caenorhabditis elegans. The RSK isoforms are downstream effectors of the Ras/ERK (extracellular-signal-regulated kinase) signalling pathway. Significant advances in the field of RSK signalling have occurred in the past few years, including several new functions ascribed to the RSK isoforms, the discovery of novel protein substrates and the implication of different RSK isoforms in cancer. Collectively, these new findings increase the diversity of biological functions regulated by RSK, and highlight potential new directions of research. In the present paper, we review the structure, expression and activation mechanisms of the RSK isoforms, and discuss their physiological roles on the basis of established substrates and recent discoveries.
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