APH02174 hemiformic
Based on 1 Customer Validation
APH02174 hemiformic is an orally effective and selective IRAK4 PROTAC degrader with a DC50 of 4.01 nM in THP-1 cells. APH02174 hemiformic inhibits LPS (HY-D1056)-induced IL-6 release by degrading IRAK4 and blocking TLR/IL-1R downstream signaling. APH02174 hemiformic exhibits favorable anti-inflammatory activity in both Imiquimod (HY-B0180)-induced psoriasis-like skin inflammation and collagen-induced arthritis models. APH02174 hemiformic is useful for research on inflammatory diseases such as psoriasis and rheumatoid arthritis.
(Pink: IRAK4 ligand (HY-174470); Blue: Cereblon ligand (HY-45512); Black: linker).
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- Formule: C49H55N7O8·1/2CH2O2
- Masse moléculaire:916.03
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Stockage:
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
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Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Activité biologique
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Chemical Information
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- Pureté et documentation
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Activité biologique
Description
IC50 & Target
[1]|
IRAK4 |
Cereblon |
IL-6 |
In Vitro
APH02174 (24 h) hemiformic effectively degrades IRAK4 in THP-1-HiBiT-IRAK4 cells with a DC50 of 4.01 nM and a Dmax of 94%[1].
APH02174 (0.05-1000 nM; 24 h) hemiformic effectively degrades IRAK4 in human PBMCs with a DC50 of 0.43 nM and a Dmax of 94%[1].
APH02174 (0.03-2000 nM; 24 h) hemiformic inhibits LPS (HY-D1056)-induced IL-6 release in human PBMCs with an IC50 of 16.43 nM[1].
APH02174 (300 nM; 24 h) hemiformic selectively degrades IRAK4 in human PBMCs[1].
APH02174 (1 μM) hemiformic does not degrade SALL4, IKZF1, or IKZF3 in human PBMCs at a concentration of 1 μM[1].
APH02174 (5 μM; 120 min) hemiformic exhibits relatively low permeability in Caco-2 cells, with a Papp (A→B) of 0.09 × 10−6 cm/s and an efflux ratio of 2.22[1].
APH02174 (10 μM; 5-30 min) hemiformic shows low inhibitory effects on CYP isozymes in human liver microsomes[1].
APH02174 (3 μM; 5 min) hemiformic exhibits moderate hERG inhibition with an inhibition rate of 53%[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:human PBMCs
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Concentration:0.24, 0.98, 3.91, 15.63, 62.50, 250.00 and 1000.00 nM
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Incubation Time:24 h
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Result:Degraded IRAK4 in human PBMCs in a concentration-dependent manner, with a DC50 of 0.43 nM and a Dmax of 94%.
Parmacokinetics
| Species | Dose | Route | Cmax | AUClast | T1/2 | CL | Vss | Tmax | F |
|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 2 mg/kg | i.v. | 1867 ng/mL | 10556 ng·h/mL | 3.78 h | 3.13 mL/min/kg | 0.880 L/kg | / | / |
| Mice[1] | 10 mg/kg | p.o. | 2073 ng/mL | 23388 ng·h/mL | 4.34 h | / | / | 2.67 h | 45 % |
| Rat[1] | 2 mg/kg | i.v. | 1420 ng/mL | 2589 ng·h/mL | 4.00 h | 12.8 mL/min/kg | 2.66 L/kg | / | / |
| Rat[1] | 30 mg/kg | p.o. | 613 ng/mL | 7093 ng·h/mL | 3.43 h | / | / | 6.00 h | 18 % |
| Dog[1] | 1 mg/kg | i.v. | 599 ng/mL | 3669 ng·h/mL | 8.10 h | 4.75 mL/min/kg | 2.73 L/kg | / | / |
| Dog[1] | 5 mg/kg | p.o. | 360 ng/mL | 6994 ng·h/mL | 10.6 h | / | / | 4.00 h | 39 % |
| Monkey[1] | 1 mg/kg | i.v. | 672 ng/mL | 1818 ng·h/mL | 8.67 h | 9.20 mL/min/kg | 3.85 L/kg | / | / |
| Monkey[1] | 20 mg/kg | p.o. | 229 ng/mL | 3997 ng·h/mL | 9.07 h | / | / | 6.00 h | 11 % |
In Vivo
APH02174 (10-100 mg/kg; p.o.; twice daily; 6 days) hemiformic dose-dependently attenuates IMQ-induced psoriasis-like skin inflammation in mice[1].
APH02174 (30-100 mg/kg; p.o.; twice daily; 14 days) hemiformic effectively alleviates arthritis symptoms in the CIA mouse model by degrading IRAK4 in PBMCs[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Cynomolgus monkeys (4 years old)[1]
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Dosage:20 mg/kg
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Administration:p.o.; single dose
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Result:Degraded 83% of IRAK4 in cynomolgus monkey PBMCs at 48 h postadministration.
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Animal Model:C57BL/6 mice (7-week-old)[1]
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Dosage:10, 30, 100 mg/kg
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Administration:p.o.; twice daily; from day 0 to day 6
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Result:Showed a dose-dependent reduction in erythema intensity and scaling, with near-complete resolution of crusts and restoration of normal skin texture at 100 mg/kg.
Decreased delta ear thickness significantly in the 10, 30, and 100 mg/kg groups.
Exhibited a significant reduction in spleen weight in the 30 and 100 mg/kg groups.
Induced dose-dependent IRAK4 degradation in splenic tissue, with 30 and 100 mg/kg achieving >80% depletion, and the 10 mg/kg dose inducing 75% degradation.
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Animal Model:DBA/1 mice (male)[1]
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Dosage:30, 100 mg/kg
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Administration:p.o.; twice daily; for 14 days
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Result:Significantly attenuated clinical scores at 30 and 100 mg/kg.
Significantly improved delta paw volume and histopathological scores at 30 and 100 mg/kg.
Markedly degraded IRAK4 in mouse PBMCs at 30 and 100 mg/kg.
Chemical Information
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Appearance Solid
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Masse moléculaire 916.03
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Formule C49H55N7O8·1/2CH2O2
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SMILES
OCC1CCN(CC1)C2=CC3=C(C=C2NC(C4=COC5=C4N=CC=C5)=O)CC6(CCN(CC6)C[C@@H]7CC[C@@H](OCC#CC8=C(C(N(C9=O)C%10C(NC(CC%10)=O)=O)=CC=C8)N9C)CC7)O3.OC=O.[1/2]
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
APH02174 hemiformic Related Classifications
HY-174455A Related Classifications
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