ESI-09 is a novel noncyclic nucleotide EPAC antagonist, showcasing selective inhibitory properties with IC50 values of 3.2 μM for EPAC1 and 1.4 μM for EPAC2, underscoring its potential in targeting these exchange proteins directly activated by cAMP[1].
体内研究
Moreover, ESI-09 treatment in wild-type (WT) mice infected with R. australis resulted in notably milder disease manifestations and significantly improved survival rates[2].
体外研究
This antagonist demonstrates enhanced efficacy in comparison to cAMP, displacing 8-NBD-cAMP binding with an apparent IC50 of 10 μM, and effectively inhibiting cAMP-mediated GEF activity of both EPAC2 and EPAC1. Additionally, ESI-09 dose-dependently suppresses 007-AM-stimulated Akt phosphorylation at T308 and S473, indicating its role in modulating key signaling pathways[1].
Beyond its anticancer potential, ESI-09 has been shown to significantly reduce both intracellular and total bacterial counts in human umbilical vein endothelial cells (HUVECs) post-infection with R. australis at a multiplicity of infection (MOI) of 10, compared to controls. This demonstrates its utility in infectious disease models, particularly in reducing bacterial burden[2].
ESI-09 prevented isoprenaline-induced adenosine release from rat detrusor strips, indicating the role of EPAC1 in β3-adrenoceptor-induced adenosine release.
Br J Pharmacol. 2020 Apr;177(7):1589-1608.
Human urothelium-denuded detrusor strips
10 µM
15 minutes
ESI-09 prevented mirabegron- and isoprenaline-induced adenosine release from human detrusor strips, indicating the role of EPAC1 in β3-adrenoceptor-induced adenosine release.
Br J Pharmacol. 2020 Apr;177(7):1589-1608.
Mouse airway smooth muscle cells (ASMCs)
1, 10, 100 µM
24, 48, 72 hours
ESI-09 promoted ASMCs proliferation at 10 and 100 μM
Respir Res. 2019 Dec 18;20(1):285.
Human umbilical vein endothelial cells (HUVECs)
5 µM
30 minutes
To evaluate the effect of ESI-09 on the attachment and invasion of Rickettsia australis into HUVECs. Results showed that ESI-09 significantly reduced intracellular and total bacterial counts.
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19615-20.
Mouse airway smooth muscle cells (ASMCs)
1, 10, 100 µM
30 minutes
ESI-09 promoted SOCE in ASMCs at 10 and 100 μM
Respir Res. 2019 Dec 18;20(1):285.
Left atrial fibroblasts
1 µM
48 hours
To evaluate the effect of Epac1 inhibition on isoproterenol's effect. ESI-09 blocked the isoproterenol-induced decrease in collagen protein expression.
Cardiovasc Res. 2019 Jan 1;115(1):94-106.
Left atrial fibroblasts
1 µM
48 hours
To evaluate the effect of Epac1 inhibition on collagen expression. ESI-09 increased COL1A1 mRNA levels by 40% and collagen I protein expression by 97%.
Cardiovasc Res. 2019 Jan 1;115(1):94-106.
A549 cells
2 µM
48 hours
Evaluate the effect of ESI-09 on lung cancer cell survival under low-glucose conditions, results showed ESI-09 significantly reduced cell survival
Mol Metab. 2020 Dec;42:101093.
Mouse airway smooth muscle cells (ASMCs)
1, 10, 100 µM
48 hours
ESI-09 had no significant effect on ASMCs apoptosis
Respir Res. 2019 Dec 18;20(1):285.
PC3 cells
2 µM
72 hours
Evaluate the effect of ESI-09 on lung cancer cell survival under low-glucose conditions, results showed ESI-09 significantly reduced cell survival
Mol Metab. 2020 Dec;42:101093.
H1975 cells
2 µM
72 hours
Evaluate the effect of ESI-09 on lung cancer cell survival under low-glucose conditions, results showed ESI-09 significantly reduced cell survival
Mol Metab. 2020 Dec;42:101093.
H1299 cells
2 µM
72 hours
Evaluate the effect of ESI-09 on lung cancer cell survival under low-glucose conditions, results showed ESI-09 significantly reduced cell survival
Mol Metab. 2020 Dec;42:101093.
MCF-7 breast cancer cells
1 µM
72 hours
ESI-09, as an EPAC inhibitor, abrogated the isoprenaline-induced lipid droplet accumulation
Int J Mol Sci. 2023 Jan 1;24(1):767.
Human atrial myocytes
10 µM
ESI-09, as an Epac inhibitor, reversed or prevented the noradrenaline-induced up-regulation of ICl.vol under hypotonic conditions
Br J Pharmacol. 2018 Aug;175(16):3422-3432.
ESI-09 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Neonatal colorectal distension (CRD)-induced visceral hypersensitivity model
Intra-PVN microinjection
1.0 μg/μl
Single injection, needle retained for 10 minutes
Inhibition of Epac1 increased the firing frequency of PVN CRF neurons, facilitated visceral hypersensitivity and pain precipitation
CNS Neurosci Ther. 2022 Sep;28(9):1393-1408
Female BALB/c mice
Acute and chronic asthma models
Intraperitoneal injection
10 mg/kg
30 min before each OVA challenge for 3 days (acute) or 6 weeks (chronic)
ESI-09 aggravated airway inflammation and airway remodeling
Respir Res. 2019 Dec 18;20(1):285.
Mice
Orthotopic metastatic PDA mouse model
Intraperitoneal injection
10 mg/kg
3 weeks
Reduced local and distant spread of MIA PaCa-2 cells and significantly decreased metastasis to the liver
J Med Chem. 2015 Aug 13;58(15):6033-47
Mice (C57BL/6)
Fatal spotted fever group (SFG) rickettsiosis model
Intraperitoneal injection
10 mg/kg/day
Once daily for 5 days before infection and 7 days after infection
To evaluate the therapeutic effect of ESI-09 on fatal SFG rickettsiosis. Results showed that ESI-09 significantly improved survival and reduced pathological damage.
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19615-20.
Mice
Epac WT, Epac1–/–, Epac2–/–, and Epac1&2–/– mice
Intraperitoneal injection
10 mg/kg
Daily injections for 7 days
To investigate the effect of ESI-09 on urinary sodium excretion in mice, results showed that ESI-09 significantly increased urinary sodium excretion under a low-sodium diet, indicating its inhibitory effect on ENaC activity.
JCI Insight. 2022 Feb 8;7(3):e145653
Rat
Urethane-anaesthetized rats
Intravesical instillation
10 μM
Single administration
Pre-treatment with ESI-09 prevented the reduction of the voiding frequency caused by isoprenaline and forskolin, indicating the role of EPAC1 in β3-adrenoceptor-induced bladder function regulation.
Br J Pharmacol. 2020 Apr;177(7):1589-1608.
BALB/c-nu (nu/nu) mice
A549 cell xenograft model
Intraperitoneal injection
2 mg/kg or 10 mg/kg
Once daily for 21 days
Evaluate the inhibitory effect of ESI-09 on tumor growth, results showed ESI-09 significantly inhibited tumor growth and reduced tumor volume
Mol Metab. 2020 Dec;42:101093.
C57Bl/6 mice
GDNF-induced hyperalgesic priming model
Oral
20 mg/kg
Administered on the 13th and 14th day
ESI-09 significantly reduced the duration of PGE2 hyperalgesia in GDNF-primed mice.
Front Pharmacol. 2018 Jun 5;9:592
C57BL/6 mice
Myocardial infarction model
Intraperitoneal injection
20 mg/kg/day
Once daily for 5 days
To evaluate the effect of Epac1 inhibition post-MI. ESI-09 did not significantly alter the heart weight to body weight ratio, LV function, or atrial fibrosis.
Cardiovasc Res. 2019 Jan 1;115(1):94-106.
Rats
Chronic morphine-induced analgesic tolerance model
Intrathecal injection
5 μg
Once daily for 7 days
ESI-09 significantly attenuated the development of morphine-induced anti-nociceptive tolerance while retaining the anti-nociceptive effect of morphine. Additionally, ESI-09 reduced the phosphorylation of PKC ε and up-regulated expression of Epac after chronic morphine exposure.
Br J Pharmacol. 2018 May;175(10):1760-1769
Mice
CFA-induced inflammatory mechanical hyperalgesia model
Oral
5, 20, or 50 mg/kg
Treatment started on the third day after CFA administration
To evaluate the inhibitory effect of ESI-09 on established CFA-induced mechanical hyperalgesia
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3036-41
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