The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps Ca2+ from the cytoplasm into the endoplasmic reticulum (ER). CDN1163 is a small-molecule allosteric activator of SERCA that acts directly on SERCA and improves Ca2+ homeostasis. CDN1163 at 1 – 11μM dose-dependently increased the Vmax of SERCA2 Ca2+-ATPase activity in the ER microsomes from liver tissues. CDN1163 at 10μM rescued cells from H2O2-stimulated cell death. In ob/ob male mice, intraperitoneal injection with 300μL of CDN1163 (50mg/kg/day) for 5 days reduced blood glucose levels and improved metabolic parameters compared with the vehicle-treated group. Treatment with CDN1163 also resulted in a 16% decrease in adipose tissue weight, reduced gluconeogenic gene expression, reversed hepatic steatosis, and inhibited ER stress and ER stress-induced apoptosis in ob/ob mice[3].
CDN1163 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mouse renal tubular epithelial cells (mRTECs)
10 µM
1 hour pretreatment followed by 24 hours treatment
CDN1163 restored Cd2+-induced reduction in ER Ca2+ content and decreased the expression of ER stress markers BiP, PDI, and apoptosis marker cleaved caspase-3
Int J Mol Sci. 2023 Mar 22;24(6):5979.
HT22 cells
10 µM
10 min
CDN1163 enhanced cytoplasmic Ca2+ clearance of SERCA2 mutants and attenuated hypo-glutamate-induced excitotoxicity
Confirmed direct interaction with SERCA protein showing ~26% increase in charge displacement
ChemMedChem. 2021 Nov 5;16(21):3293-3299.
Rabbit skeletal muscle SR vesicles
10 µM
15 minutes
CDN1163 significantly enhanced ATP-dependent Ca2+ translocation by SERCA with ~30% increase in charge displacement
ChemMedChem. 2021 Nov 5;16(21):3293-3299.
Jurkat T lymphocytes
10 µM
20 min
Short-term exposure to CDN1163 significantly increased Ca2+ release responses induced by low-dose tBHQ, indicating enhanced Ca2+ release from the SERCA 3-regulated Ca2+ pool.
Int J Mol Sci. 2024 Nov 11;25(22):12095.
HT22 mouse hippocampal neurons
1 µM
24 hours
CDN1163 significantly alleviated heat stress-induced calcium imbalance, reduced cytoplasmic Ca2+ levels and elevated ER Ca2+ levels, inhibited p-PERK and p-eIF2α protein expression, effectively attenuating endoplasmic reticulum stress and apoptosis.
Cell Death Discov. 2024 Jun 11;10(1):280.
H1395 cells
10 µM
24 hours
CDN1163 attenuated mitochondrial dysfunction in IAV-infected H1395 cells.
J Virol. 2021 Apr 26;95(10):e00217-21.
H9c2 cells
10 µM
24 hours
CDN1163 markedly abolished glucose-stimulated NFATc nuclear translocation, reduced resistin and nuclear NFATc expression, and increased AMPKα phosphorylation.
Sci Rep. 2018 Oct 23;8(1):15633.
HEK cells
10 µM
2-hours pretreatment followed by 16-hours exposure to H2O2
To evaluate the rescue effect of CDN1163 on ER stress-induced cell death; CDN1163 significantly attenuated H2O2-stimulated cell death
J Biol Chem. 2016 Mar 4;291(10):5185-98.
Jurkat T lymphocytes
25 µM
30 min
Short-term exposure to CDN1163 significantly inhibited Ca2+ uptake, suggesting SERCA function was suppressed.
Int J Mol Sci. 2024 Nov 11;25(22):12095.
H2K-mdx myotubes
100 µM
30 minutes
CDN1163 significantly reduced cytosolic Ca2+ levels in H2K-mdx myotubes
Hum Mol Genet. 2021 May 31;30(11):1006-1019.
Lymphatic muscle cells (LMCs)
5 µM
48 hours
To evaluate the effect of CDN1163 on SERCA activity in insulin-resistant LMCs. Results showed that CDN1163 partially restored the contractile frequency of lymphatic vessels.
Sci Rep. 2020 Jul 23;10(1):12320.
Jurkat T lymphocytes
10 µM
72 hours
Long-term exposure to CDN1163 increased Ca2+ store levels in the SERCA 2b pool but decreased store levels in the SERCA 3-regulated pool.
Int J Mol Sci. 2024 Nov 11;25(22):12095.
CDN1163 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Diabetic Mice model (db/db mice)
Intraperitoneal injection
100 mg/kg
5 consecutive days
CDN1163 improved glucose tolerance, hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice.
Cells. 2022 Apr 28;11(9):1488
C57BL/6 mice
Heat stress-induced cognitive impairment model
Intraperitoneal injection
20 mg/kg
Once daily for 7 days
CDN1163 upregulated SERCA expression, restored Ca2+ homeostasis, improved learning and memory abilities, and alleviated hippocampal neuronal damage and endoplasmic reticulum stress-mediated apoptosis.
Cell Death Discov. 2024 Jun 11;10(1):280.
Mdx mice
Duchenne muscular dystrophy model
Intraperitoneal injection
40 mg/kg
Three times per week for 7 weeks
CDN1163 ameliorated dystrophic phenotypes in mdx mice, including reduced muscle degeneration and fibrosis, enhanced muscle strength, and restored mitochondrial function
Hum Mol Genet. 2021 May 31;30(11):1006-1019.
Ob/ob mice (obese/diabetic model)
Insulin resistance and type 2 diabetes model
Intraperitoneal injection
50 mg/kg
Once daily for 5 consecutive days
To evaluate the effects of CDN1163 on blood glucose and metabolic parameters; CDN1163 significantly reduced fasting blood glucose, improved glucose tolerance, ameliorated hepatic steatosis, increased energy expenditure, and upregulated UCP1 and UCP3 expression in brown adipose tissue. Effects persisted for >6 weeks post-treatment.
J Biol Chem. 2016 Mar 4;291(10):5185-98.
Ob/ob mice
Diabetic mice model
Intraperitoneal injection
50 mg/kg
3× /week for 30 days
CDN1163 treatment significantly decreased resistin and nuclear NFATc protein expression and increased AMPKα activity/phosphorylation.
Sci Rep. 2018 Oct 23;8(1):15633.
Mice
CuZnSOD deficient Mice model
Intraperitoneal injection
50 mg/kg
Three times per week for 7 weeks
CDN1163 completely restored SERCA activity and reversed the 23% reduction in gastrocnemius mass and 22% reduction in specific force in untreated Sod1-/- versus wild type mice. These changes were accompanied by restoration of autophagy protein markers to the levels found in wild-type mice. CDN1163 also reversed the increase in mitochondrial ROS generation and oxidative damage in muscle tissue from Sod1-/- mice.
Redox Biol. 2019 Jan;20:68-74
Mice
Wild-type (WT) and melanocortin-4 receptor knockout (Mc4r−/−) mice
Injections
50 mg/kg
Once every 2 weeks for 8 weeks (four total doses); or three times per week for 8 weeks (24 total doses)
Studied the effects of CDN1163 on diet-induced steatohepatitis, showing that CDN1163 improved liver fibrosis and inflammation, restored glucose tolerance and insulin sensitivity, increased antioxidant enzyme expression, and decreased oxidative stress and ER stress gene expression.
J Lipid Res. 2024 Jun;65(6):100558
Wistar rats
Hindlimb unloading/suspension model
Intraperitoneal injection
50 mg/kg
Once daily for 7 days
Treatment with SERCA activator CDN1163 during 7 days of unloading prevented an increase in soleus fatigue, the decrease of slow-type myosin, mitochondrial markers, and markers of calcium homeostasis but had no effect on muscle atrophy.
Biomolecules. 2023 Sep 6;13(9):1354
C57BL/6J mice
Aged mice
Intra-peritoneal injection
50 mg/kg
Three times per week for 10 months
CDN1163 treatment via diet and injection prevented age-related muscle atrophy and weakness, restored SERCA ATPase activity, and improved mitochondrial function.
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