APH003
APH003 is an orally active IRAK4 PROTAC degrader with a DC50 of 0.74 nM in human peripheral blood mononuclear cells (hPBMCs). APH003 recruits IRAK4 to CRBN to form a ternary complex, mediates the ubiquitination and degradation of IRAK4 via the ubiquitin-proteasome pathway, and inhibits the kinase activity of IRAK4. APH003 inhibits LPS- or IL-1β/LPS-induced phosphorylation of ERK, JNK and NF-κB. APH003 inhibits the secretion of TNF-α, IL-6, IL-8 and IL-13 by stimulated hPBMCs. APH003 exhibits anti-inflammatory activity in rat TNBS-induced intestinal inflammation models and mouse IL-33-induced skin inflammation models. APH003 can be used in research related to inflammatory bowel disease and skin inflammation.
(Pink: IRAK4 ligand (HY-184916); Blue: Cereblon ligand (HY-49385); Black: linker).
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- CAS No.: 3065495-08-8
- Formule: C44H50FN11O7
- Masse moléculaire:863.94
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Activité biologique
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IRAK4 1.13 nM (IC50) |
IRAK4 4.76 nM (EC50) |
IRAK4 75.26 nM (Kd) |
ERK |
NF-κB |
JNK |
IL-1β |
IL-6 |
IL-8 |
IL-13 |
APH003 (10-point concentration gradient; 60 min) potently inhibits purified IRAK4 kinase, with an IC50 of 1.13 nM[1].
APH003 (0.001-10000 nM; 15 min) binds to purified CRBN with a Kd value of 75.26 nM[1].
APH003 (0.001-1000 nM; 60 min) promotes the formation of the IRAK4-PROTAC-CRBN ternary complex, with an EC50 of 4.76 nM[1].
APH003 (0.05-1000 nM; 2-48 h) degrades IRAK4 in human peripheral blood mononuclear cells (hPBMCs) via the CRBN-ubiquitin-proteasome pathway, with a 24 h DC50 of 0.74 nM, and its potency increases in a time-dependent manner within 48 h[1].
APH003 (0.05-1000 nM; 24 h) degrades IRAK4 in mouse, rat and canine PBMCs, with corresponding DC50 values of 5.06 nM, 2.24 nM and 3.88 nM, respectively, and its potency is lower than that in human PBMCs (hPBMCs)[1].
APH003 (0.05-1000 nM; 24 h pretreatment, 30 min LPS stimulation) inhibits LPS-induced phosphorylation of ERK, JNK, and NF-κB in human peripheral blood mononuclear cells (hPBMCs), with IC50 values of 31.1 nM, 206.5 nM, and 353.8 nM, respectively[1].
APH003 (0.03-2000 nM; 24 h pretreatment, 24 h LPS stimulation) inhibits LPS-induced secretion of TNF-α and IL-6 in human peripheral blood mononuclear cells (hPBMCs), with IC50 values of 3.84 nM and 2.86 nM, respectively[1].
APH003 (0.03-2000 nM; 24 h pretreatment, 24 h costimulation) inhibits the secretion of TNF-α, IL-6, IL-8 and IL-13 in human peripheral blood mononuclear cells (hPBMCs) stimulated by IL-1β + LPS, with corresponding IC50 values of 12.06 nM, 17.34 nM, 112.92 nM and 43.27 nM, respectively[1].
APH003 (10-1000 nM; 24 h) selectively degrades IRAK4 in human peripheral blood mononuclear cells (hPBMCs), and does not affect IRAK family isoforms or novel CRBN substrates even at a concentration of 1000 nM[1].
APH003 (60 nM; 24 h) exhibits highly selective degradation of IRAK4 in human peripheral blood mononuclear cells (hPBMCs), with minimal effects on other cellular proteins[1].
APH003 exhibits excellent metabolic stability (T1/2 > 371 min) in human, monkey and dog hepatocytes, and moderate stability in rat and mouse hepatocytes[1].
APH003 exhibits weak inhibitory effects on human CYP subtypes, indicating a low potential for drug-drug interactions mediated by CYP inhibition[1].
APH003 exhibits moderate Caco-2 permeability with an efflux ratio of 7.36, suggesting that it may be a substrate of efflux transporters[1].
APH003 shows low solubility in neutral/weakly acidic media but high solubility in acidic FaSSGF, which supports its potential oral absorbability[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:0.05 nM, 0.15 nM, 0.46 nM, 1.37 nM, 4.12 nM, 12.35 nM, 37.04 nM, 111.11 nM, 333.33 nM, 1000.00 nM
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Incubation Time:24 h
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Result:Inhibited LPS-induced phosphorylation of ERK, JNK, and NF-κB in human peripheral blood mononuclear cells (hPBMCs).
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Cell Line:Human PBMCs
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Concentration:10 nM, 100 nM, 100 nM
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Incubation Time:24 h
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Result:Selectively degraded IRAK4 in human peripheral blood mononuclear cells (hPBMCs).
Did not affect IRAK family isoforms or novel CRBN substrates even at a concentration of 1000 nM.
| Species | Dose | Route | Cmax | AUClast | T1/2 | CL | Vss | Tmax | F |
|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 2 mg/kg | i.v. | 3270 ng/mL | 12939 ng·h/mL | 4.68 h | 1.88 mL/min/kg | 0.749 L/kg | / | / |
| Mice[1] | 10 mg/kg | i.g. | 4830 ng/mL | 38237 ng·h/mL | 11.3 h | / | / | 1.00 h | 68 % |
| Rat[1] | 2 mg/kg | i.v. | 1245 ng/mL | 4500 ng·h/mL | 1.46 h | 7.40 mL/min/kg | 0.729 L/kg | / | / |
| Rat[1] | 30 mg/kg | i.g. | 3563 ng/mL | 31463 ng·h/mL | 2.78 h | / | / | 2.00 h | 46 % |
| Dog[1] | 1 mg/kg | i.v. | 548 ng/mL | 3367 ng·h/mL | 12.2 h | 4.69 mL/min/kg | 3.84 L/kg | / | / |
| Dog[1] | 5 mg/kg | i.g. | 491 ng/mL | 10119 ng·h/mL | 14.4 h | / | / | 4.00 h | 63 % |
| Cynomolgus Monkey[1] | 1 mg/kg | i.v. | 680 ng/mL | 2978 ng·h/mL | 10.5 h | 5.43 mL/min/kg | 3.68 L/kg | / | / |
| Cynomolgus Monkey[1] | 20 mg/kg | i.g. | 1423 ng/mL | 18843 ng·h/mL | 11.3 h | / | / | 4.00 h | 32 % |
APH003 (3-30 mg/kg; p.o.; twice daily; 11 days) dose-dependently suppresses IL-33-induced skin inflammation in mice, with a 68% inhibition of delta ear thickness AUC0-t and 97% inhibition of ear tissue IL-5 secretion at the 30 mg/kg twice-daily oral dose, accompanied by IRAK4 degradation in circulating WBCs[1].
APH003 (3-100 mg/kg; p.o.; daily; 7 days) dose-dependently degrades IRAK4 in rat skin and PBMCs after repeated oral administration, achieving 91% IRAK4 degradation in skin at the 100 mg/kg daily dose[1].
APH003 (0.3-3 mg/kg; p.o.; daily; 7 days) degrades IRAK4 in dog PBMCs and skin after repeated oral administration, achieving 88% IRAK4 degradation in skin at the 3 mg/kg daily dose after 7 days, with skin degradation showing no consistent dose-dependent trend across the tested doses[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague-Dawley (SD) rats (male)[1]
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Dosage:10 mg/kg; 30 mg/kg; 100 mg/kg
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Administration:p.o.; daily; 8 days
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Result:Significantly alleviated TNBS-induced weight loss on day 8, reduced DAI scores starting on day 6, and inhibited the AUC of DAI scores by 37% at 10 mg/kg.
Reduced DAI scores starting on day 3, and inhibited the AUC of DAI scores by 56% at 30 mg/kg.
Significantly alleviated weight loss from day 5 to day 8, reduced DAI scores starting on day 3, and inhibited the AUC of DAI scores by 64% at 100 mg/kg.
Degraded IRAK4 in rat colon tissue by 94% at 10 mg/kg, 92% at 30 mg/kg, and 94% at 100 mg/kg.
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Animal Model:male[1]
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Dosage:3 mg/kg; 10 mg/kg; 30 mg/kg
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Administration:p.o.; twice daily; 11 days
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Result:Reduced delta ear thickness in a dose-dependent manner; at 30 mg/kg, almost completely eliminated IL-33-induced ear inflammation by day 11.
Inhibited the AUC of delta ear thickness by 52% at 3 mg/kg, 55% at 10 mg/kg, and 68% at 30 mg/kg.
Inhibited IL-5 secretion in ear tissue by 59% at 3 mg/kg, 55% at 10 mg/kg, and 97% at 30 mg/kg; in plasma, inhibited IL-5 secretion by 55% at 3 mg/kg, 61% at 10 mg/kg, and 96% at 30 mg/kg.
Degraded IRAK4 in WBCs by 53% at 3 mg/kg, 68% at 10 mg/kg, and 71% at 30 mg/kg.
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Animal Model:Sprague-Dawley (SD) rats (male)[1]
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Dosage:3 mg/kg; 100 mg/kg
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Administration:p.o.; daily; 7 days
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Result:Degraded IRAK4 in rat skin by 55% 24 hours after the seventh dose; in PBMCs, degraded IRAK4 by 78% at 6 hours and 75% at 24 hours after the first dose, and by 76% at 6 hours and 71% at 24 hours after the seventh dose at 3 mg/kg.
Degraded IRAK4 in rat skin by 91% 24 hours after the seventh dose; in PBMCs, degraded IRAK4 by 92% at 6 hours and 91% at 24 hours after the seventh dose at 100 mg/kg.
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Animal Model:Beagle dogs (male)[1]
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Dosage:0.3 mg/kg; 1 mg/kg; 3 mg/kg
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Administration:p.o.; daily; 7 days
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Result:Degraded IRAK4 in dog PBMCs by 78% 24 hours after the first dose and 60% 24 hours after the seventh dose; in skin, degraded IRAK4 by 41% 24 hours after the first dose and 37% 24 hours after the seventh dose at 0.3 mg/kg.
Degraded IRAK4 in dog PBMCs by 82% 24 hours after the first dose and 72% 24 hours after the seventh dose; in skin, degraded IRAK4 by 41% 24 hours after the first dose and 22% 24 hours after the seventh dose at 1 mg/kg.
Degraded IRAK4 in dog PBMCs by 82% 24 hours after the first dose and 83% 24 hours after the seventh dose; in skin, degraded IRAK4 by 31% 24 hours after the first dose and 88% 24 hours after the seventh dose at 3 mg/kg.
Chemical Information
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CAS No. 3065495-08-8
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Masse moléculaire 863.94
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Formule C44H50FN11O7
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SMILES
FC1=C(C=C2N(N=C(C2=C1)N3C(NC(CC3)=O)=O)C)N4CCC(O)(CC4)CC(N5CCC6(CC5)CC7=C(O6)C=C(N8CCC(CC8)CO)C(NC(C9=C%10N=CC=CN%10N=C9)=O)=C7)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
APH003 Related Classifications
HY-184915 Related Classifications
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