PDK1 (3-phosphoinositide-dependent protein kinase 1) plays an important role in growth factor signalling cascades by phosphorylating and activating a group of protein kinases belonging to the AGC [PKA (protein kinase A)/PKG (proteinkinase G)/PKC (protein kinase C)]-kinase family. GSK2334470 inhibits PDK1 with an IC₅₀ of ~10 nM. Addition of GSK2334470 to HEK (human embryonic kidney)-293, U87 or MEF (mouse embryonic fibroblast) cells ablated T-loop residue phosphorylation and activation of SGK isoforms and S6K1 induced by serum or IGF1 (insulin-like growth factor 1). GSK2334470 also inhibited T-loop phosphorylation and activation of Akt, but was more efficient at inhibiting Akt in response to stimuli such as serum that activated the PI3K (phosphoinositide 3-kinase) pathway weakly. GSK2334470 inhibited activation of an Akt1 mutant lacking the PH domain (pleckstrin homology domain) more potently than full-length Akt1, suggesting that GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2 (p90 ribosomal S6 kinase 2), another PDK1 target activated by the ERK (extracellular-signal-regulated kinase) pathway[2]. Furthermore, chemical inhibition of PDK1 using the specific inhibitor GSK2334470 (1 µM) resulted in total abrogation of the EGF-induced intracellular calcium increase and inositol phosphates accumulation in MDA-MB-231 cells[3].
GSK2334470 细胞实验
Cell Line
Concentration
Treated Time
Description
References
CD4 T cells
2.5 mM
3 days
GSK significantly attenuated HS-induced phosphorylation of PDPK1 and SGK1, and corrected the Th17 enhancement and Treg impediment triggered by HS
iScience. 2024 Apr 26;27(6):109798.
CD4 T cells
5 mM, 10 mM
3 days
GSK significantly increased CD4 T cell apoptosis and inhibited their proliferation
iScience. 2024 Apr 26;27(6):109798.
ER+ breast cancer cell lines
1 µM
72 hours
To synergistically inhibit proliferation and increase apoptosis
Cancer Res. 2017 May 1;77(9):2488-2499.
LAN-1-MK cells
5 µM
72 hours
GSK2334470 significantly inhibited the growth of LAN-1-MK cells and induced G0-G1 phase cell accumulation.
Cancer Cell Int. 2015 Sep 29;15:91.
KP-N-SIFA-MK cells
5 µM
72 hours
GSK2334470 significantly inhibited the growth of KP-N-SIFA-MK cells and induced G0-G1 phase cell accumulation.
Cancer Cell Int. 2015 Sep 29;15:91.
SK-N-DZ-MK cells
5 µM
72 hours
GSK2334470 significantly inhibited the growth of SK-N-DZ-MK cells and induced G0-G1 phase cell accumulation.
Cancer Cell Int. 2015 Sep 29;15:91.
GSK2334470 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
MCF-7 xenograft model
Intraperitoneal injection
100 mg/kg
Three times per week for 6 weeks
To determine the efficacy in decreasing tumor growth
Cancer Res. 2017 May 1;77(9):2488-2499.
DBA/1 mice
Collagen-induced arthritis model
Intraperitoneal injection
25 mg/kg
Every three days for 21 days
GSK significantly alleviated HS diet-exacerbated arthritis symptoms and corrected the Th17/Treg imbalance
Antiproliferative activity against human F-36P cells, IC50=0.28 μM
21341675
insect cells
Function assay
Inhibition of recombinant full length PDK1 (unknown origin) expressed in insect cells assessed as inhibition of Akt activation measured for 30 mins in presence of [gamma32P-ATP], IC50=0.01 μM
23448267
K562 cells
Proliferation assay
Antiproliferative activity against human K562 cells, IC50=18 μM
21341675
OCI-AML2 cells
Proliferation assay
Antiproliferative activity against human OCI-AML2 cells, IC50=0.35 μM
21341675
OCI-AML3 cells
Proliferation assay
Antiproliferative activity against human OCI-AML3 cells, IC50=0.52 μM
21341675
PC3 cells
Function assay
Inhibition of PDK1-mediated AKT phosphorylation at Thr308 residue in human PC3 cells by ELISA, IC50=0.113 μM
21341675
PC3 cells
Function assay
Inhibition of PDK1-mediated RSK phosphorylation at Ser221 residue in human PC3 cells by ELISA, IC50=0.293 μM
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