CID755673 is the first potent and selective cell-active small molecule PKD inhibitor with IC50 value of 182nM for inhibition of PKD1 enzyme activity. Pretreatment with CID755673 for 45min at 50μM blocked PMA-induced endogenous PKD1 activation shown by phosphorylation at Ser742 and Ser916 in LNCaP cells. Further study showed that CID755673 inhibited the known biological actions of PKD1 including PMA- induced class IIa histone deacetylase 5 nuclear exclusion, vesicular stomatitis virus glycoprotein transport from the Golgi to the plasma membrane, and the ilimaquinone-induced Golgi fragmentation. Significant inhibition of prostate cancer cell proliferation, cell migration, and invasion could be observed post treatment with 25μM CID755673. Treatment with CID755673 at concentration ranging in 10-200μM indeed resulted in a significant dose-dependent reduction of NK cell degranulation markers and cytokine release in freshly isolated Peripheral blood mononuclear cell populations from healthy blood donors.
CID755673 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Bone marrow macrophages (BMMs)
10 μM
16 h
Inhibited the motility of preosteoclasts, reducing the number of migrated cells in transwell assays.
Int J Mol Sci. 2020 Feb 5;21(3):1056
Bone marrow macrophages (BMMs)
30 μM
4 days
Inhibited the differentiation of committed osteoclast precursors into multinucleated mature osteoclasts, reducing the number of TRAP-positive multinucleated osteoclasts and the number of nuclei per osteoclast.
Int J Mol Sci. 2020 Feb 5;21(3):1056
rat pancreatic acinar cells
25μM
3 h
To test the effect of ethanol and low-dose CCK-8 on PKD1 phosphorylation and the inhibitory effect of PKD inhibitors CID or CRT. Results showed that the combination of ethanol and CCK-8 significantly enhanced PKD1 phosphorylation, and pretreatment with CID or CRT effectively inhibited this enhancement.
Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166486
HeLa cells
5 µM
30 min
Inhibition of ilimaquinone-induced Golgi fragmentation
J Biol Chem. 2008 Nov 28;283(48):33516-26
LNCaP cells
50 µM
20 min
Inhibition of PMA-induced PKD1 phosphorylation
J Biol Chem. 2008 Nov 28;283(48):33516-26
BMM cultures
10 µM and 30 µM
5-6 days
To assess the effect of PKD inhibition on maturation of multinucleated osteoclasts. Results showed that CID755673 treatment reduced the number and size of TRAP-positive multinucleated cells.
J Biol Chem. 2013 Apr 5;288(14):9826-9834
bone marrow macrophages
10 µM and 30 µM
3 days
To assess the effect of PKD inhibition on induction of TRAP-positive preosteoclasts. Results showed that CID755673 treatment had no significant effect on the number of TRAP-positive mononucleated cells.
J Biol Chem. 2013 Apr 5;288(14):9826-9834
LNCaP prostate cancer cells
11.8 μM
Inhibition of PKD1 autophosphorylation
ACS Med Chem Lett. 2011 Feb 14;2(2):154-159
pancreatic acinar cells
25 µM
2 h
inhibition of PKD activation and NF-κB activation
Front Physiol. 2017 Dec 7;8:1014
LNCaP cells
11.8 µM
20 min
Evaluate the inhibitory effect of CID755673 on PKD1 autophosphorylation
Pharmaceutics. 2011;3(2):186-228
Purified NK cells
5-200 μM
2 h (degranulation) and 6 h (cytokine release)
To evaluate the effect of CID755673 on degranulation and cytokine release in purified NK cells. Results showed that CID755673 had a weaker effect on degranulation but significantly inhibited cytokine release at high concentrations. Additionally, significant donor variations were observed.
Front Immunol. 2013 Mar 18;4:66
NK cells in human peripheral blood mononuclear cells (PBMCs)
5-100 μM
2 h (degranulation) and 6 h (cytokine release)
To evaluate the effect of CID755673 on NK cell degranulation and cytokine release. Results showed that CID755673 significantly inhibited NK cell degranulation and cytokine release, with IFN-γ production almost completely abrogated.
Front Immunol. 2013 Mar 18;4:66
CID755673 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Alcoholic pancreatitis model
Intraperitoneal injection
20mg/kg
Single injection, 60 minutes before pancreatitis induction
To evaluate the therapeutic effect of PKD inhibitors CID or CRT on alcoholic pancreatitis. Results showed that pretreatment with CID or CRT significantly reduced ethanol diet-enhanced PKD phosphorylation and catalytic activity, inhibited NF-κB activation and inflammatory responses, and decreased cell necrosis and the severity of pancreatitis.
Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166486
Sprague-Dawley rats
Cerulein-induced pancreatitis model
Intraperitoneal injection
15 mg/kg
Single dose 60 minutes prior
Inhibition of PKD activation and NF-κB activation, attenuation of pancreatitis severity
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