PROTAC HPK1 Degrader-3
Based on 1 Customer Validation
PROTAC HPK1 Degrader-3 is an orally active HPK1 PROTAC degrader with a DC50 of 21.26 nM. PROTAC HPK1 Degrader-3 induces HPK1 degradation via the ubiquitin-proteasome system and forms a stable ternary complex with HPK1 and CRBN. PROTAC HPK1 Degrader-3 inhibits the SLP76 and NF-κB signaling pathways, enhances the transduction of the MAPK signaling pathway, and promotes the secretion of T cell immune cytokines. PROTAC HPK1 Degrader-3 inhibits tumor growth and enhances the anti-tumor efficacy of anti-PD-L1 therapy. PROTAC HPK1 Degrader-3 can be used in the research of colon cancer.
(Pink: HPK1 ligand (HY-162842); Blue: Cereblon ligand (HY-14658); Black: linker (HY-40146)).
Para uso exclusivo en investigación. No vendemos a pacientes.
- Pureza: 98.11%
- Fòrmula: C43H42N8O5
- Peso molecular:750.84
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Almacenamiento:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Actividad biológica
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Chemical Information
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Solvente y solubilidad
- Pureza y Documentación
- Referencias
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Help & FAQs
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Actividad biológica
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HPK1 |
NF-κB |
p38 MAPK |
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| T-cell | EC50 |
12.87 nM
Compound: C3
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Immunostimulatory activity in human T cell assessed as increase in IL-2 secretion
Immunostimulatory activity in human T cell assessed as increase in IL-2 secretion
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[PMID: 39084610] |
PROTAC HPK1 Degrader-3 (compound C3) (1.5-50000 nM; 24 h) potently degrades HPK1 in Jurkat cells via the ubiquitin-proteasome system, with a DC50 of 21.26 nM and a Dmax of 80.50%[1].
PROTAC HPK1 Degrader-3 forms a stable ternary complex with HPK1 and CRBN, which is supported by a docking score of -265.68 kcal/mol and a variety of favorable intermolecular interactions[1].
PROTAC HPK1 Degrader-3 (4-10000 nM; 24 h) shows no cytotoxicity against Jurkat cells even at concentrations as high as 10 μM[1].
PROTAC HPK1 Degrader-3 (10-10000 nM; 24 h) potently induces the secretion of IL-2 and IFN-γ in anti-CD3/CD28-stimulated Jurkat cells, and completely reverses the immunosuppressive effects mediated by PGE2 and NECA[1].
PROTAC HPK1 Degrader-3 (0.01-100000 nM) potently activates IL-2 secretion in human primary T cells, with an EC50 of 12.87 nM[1].
PROTAC HPK1 Degrader-3 inhibits HPK1 kinase activity. It activates T cell function in Jurkat cells by inhibiting the SLP76-NF-κB signaling pathway and enhancing the TCR-MAPK (JNK, ERK) signaling pathway[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Jurkat T cells
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Concentration:1.5, 4.6, 14, 41, 123, 370, 1111, 3333, 10000, 25000, 50000 nM (24 h degradation assay)
1 μM (kinetic studies, 0-48 h)
1 μM (24 h with 6 h inhibitor pre-treatment)
1 μM (0-24 h with 1 μM CHX co-treatment) -
Incubation Time:24 h (degradation assay)
0, 1, 2, 4, 8, 12, 16, 24, 36, 48 h (kinetic studies)
24 h with 6 h pre-treatment (mechanistic studies)
0, 4, 8, 16, 20, 24 h (CHX co-treatment) -
Result:Induced HPK1 degradation with a DC50 of 21.26 nM and a maximum degradation (Dmax) of 80.50% after 24 h treatment.
Achieved maximal HPK1 degradation by 24 h of treatment with 1 μM of the compound.
Was completely blocked from inducing HPK1 degradation by pretreatment with proteasome inhibitor MG132 or NEDD8-activating E1 enzyme inhibitor MLN4924.
Was inhibited from inducing HPK1 degradation by pretreatment with HPK1 inhibitor 10 or thalidomide.
Effectively downregulated HPK1 by the 4 h time point when co-treated with CHX.
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Cell Line:Jurkat T cells
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Concentration:10, 100, 1000, 10000 nM (24 h with anti-CD3/CD28 stimulation)
10, 100, 1000, 10000 nM (24 h with 8 h pre-treatment of 2 nM PGE2 (HY-101952) + 2 μM NECA (HY-103173) and anti-CD3/CD28 stimulation) -
Incubation Time:24 h (anti-CD3/CD28 stimulation)
24 h with 8 h pre-treatment (immunosuppressive reversal studies) -
Result:Induced dose-dependent increases in IL-2 and IFN-γ secretion, significantly outperforming the warhead inhibitor 10 at all tested concentrations.
Increased IL-2 concentration to ~1100 pg/mL and IFN-γ concentration to ~450 pg/mL at 10000 nM with anti-CD3/CD28 stimulation.
Completely reversed immunosuppression by PGE2 and NECA, restoring IL-2 levels to ~800 pg/mL and IFN-γ levels to ~200 pg/mL at 10000 nM, while inhibitor 10 had minimal effect.
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Cell Line:Jurkat T cells
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Concentration:4, 20, 80, 400, 2000, 10000 nM
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Incubation Time:24 h
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Result:Showed no significant cytotoxicity in Jurkat cells even at 10000 nM, with survival rates remaining near 100%.
| Species | Dose | Route | T1/2 | Tmax | Cmax | AUC0-t | MRT |
|---|---|---|---|---|---|---|---|
| Rat[1] | 10 mg/kg | p.o. | 6.58 h | 1.00 h | 2085.95 ng/mL | 16383.59 ng·h/mL | 9.62 h |
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:ICR mice (3-4 weeks, CT-26 cells (3×106) in 0.1 mL medium)[1]
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Dosage:25 mg/kg (monotherapy)
25 mg/kg (combination with anti-PD-L1 antibody 5 mg/kg) -
Administration:p.o.; daily; 15 days (monotherapy)
p.o.; daily; 15 days in combination with i.p.; every 3 days; 15 days (anti-PD-L1 antibody) -
Result:Achieved a tumor growth inhibition (TGI) rate of 47.22%.
Enhanced tumor growth inhibition to a TGI rate of 65.58% when combined with anti-PD-L1 antibody.
Caused no changes in body weight after 15 consecutive days of administration.
Chemical Information
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Appearance Solid
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Peso molecular 750.84
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Fòrmula C43H42N8O5
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Color Light yellow to yellow
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SMILES
CN(C(C(C=CC(C1=CNC2=C1N=C(C=N2)C3=CC=C(C=C3)C4CCN(CC4)C5CN(C6=CC=C7C(C(N(C7=O)C8C(NC(CC8)=O)=O)=O)=C6)C5)=C9)=C9C)=O)C
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvente y solubilidad
DMSO : 100 mg/mL (133.18 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Pureza y Documentación
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Ficha de datos (278 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Instrucciones de manejo (2659 KB)
Referencias
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
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| DMSO | 1 mM | 1.3318 mL | 6.6592 mL | 13.3184 mL | 33.2960 mL |
| 5 mM | 0.2664 mL | 1.3318 mL | 2.6637 mL | 6.6592 mL | |
| 10 mM | 0.1332 mL | 0.6659 mL | 1.3318 mL | 3.3296 mL | |
| 15 mM | 0.0888 mL | 0.4439 mL | 0.8879 mL | 2.2197 mL | |
| 20 mM | 0.0666 mL | 0.3330 mL | 0.6659 mL | 1.6648 mL | |
| 25 mM | 0.0533 mL | 0.2664 mL | 0.5327 mL | 1.3318 mL | |
| 30 mM | 0.0444 mL | 0.2220 mL | 0.4439 mL | 1.1099 mL | |
| 40 mM | 0.0333 mL | 0.1665 mL | 0.3330 mL | 0.8324 mL | |
| 50 mM | 0.0266 mL | 0.1332 mL | 0.2664 mL | 0.6659 mL | |
| 60 mM | 0.0222 mL | 0.1110 mL | 0.2220 mL | 0.5549 mL | |
| 80 mM | 0.0166 mL | 0.0832 mL | 0.1665 mL | 0.4162 mL | |
| 100 mM | 0.0133 mL | 0.0666 mL | 0.1332 mL | 0.3330 mL |
PROTAC HPK1 Degrader-3 Related Classifications
HY-162816 Related Classifications
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