DD205-291
DD205-291 is a selective, orally active HPK1 PROTAC degrader with a DC50 of 8.8 nM. By inducing complete degradation of HPK1 protein, DD205-291 simultaneously blocks both its kinase-dependent functions and non-kinase scaffold functions. DD205-291 inhibits the phosphorylation of SLP-76 with an EC50 of 22.98 nM. DD205-291 induces the production of IL-2 and IFN-γ with EC50 values of 34.68 nM and 32.6 nM, respectively. Combined with anti-PD1 in mouse models, DD205-291 exerts tumor-suppressive effects with favorable safety profiles. DD205-291 can be used in colon cancer-related research.
(Pink: HPK1 ligand (HY-168283); Blue: Cereblon ligand (HY-W115490); Black: linker).
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- No. CAS: 3047066-15-6
- Fòrmula: C38H38ClF3N10O3
- Peso molecular:775.22
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Almacenamiento:
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Actividad biológica
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HPK1 8.8 nM (DC50) |
SLP-76 22.98 nM (EC50) |
IL-2 34.68 nM (EC50) |
DD205-291 (24 h) potently degrades HPK1 in Jurkat cells with a DC50 of 8.8 nM and a Dmax of 94%[1].
DD205-291 (24 h) specifically inhibits p-SLP76 (Ser376) in Jurkat cells with a DC50 of 5.63 nM and a Dmax of 82.07%[1].
DD205-291 (1 μM; 4-72 h) degrades HPK1 in Jurkat cells in a time-dependent manner, reaching 55.61% degradation at 1 μM after 4 hours[1].
DD205-291 (0.01-1 μM; 24 h) HPK1 degradation activity in Jurkat cells is dependent on ubiquitination, CRBN binding, and proteasome-mediated degradation[1].
DD205-291 (0-1000 nM; 24 h) selectively degrades HPK1 in Jurkat cells and shows no significant degradation activity against MAP4K family proteins GCK, GLK, or HGK[1].
DD205-291 exhibits low Caco-2 permeability, high plasma protein binding across species, no CYP inhibition, and good metabolic stability in hepatic microsomes and hepatocytes across multiple species[1].
DD205-291 (3 μM; ~5 minutes) has a minor inhibitory effect (4.36% inhibition) on hERG channels at 3 μM, indicating low cardiotoxicity risk[1].
DD205-291 (24 h) stimulates IL-2 secretion in human PBMCs with an EC50 of 34.68 nM and an Emax of 1151.57 pg/mL[1].
DD205-291 (48 h) enhances IFN-γ release in human Pan-T cells with an EC50 of 32.6 nM and an Emax of 1622.95 pg/mL[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Jurkat cells
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Concentration:1 μM
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Incubation Time:0, 4, 8, 16, 24, 48 and 72 h
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Result:Degraded HPK1 in a time-dependent manner; achieved 55.61% HPK1 degradation after 4 hours of incubation at 1 μM.
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Cell Line:Jurkat cells
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Concentration:0.01 and 1 μM (this compound); 0.1 and 0.3 μM (MLN4924 (HY-70062)); 0.05 and 0.1 μM (MG132 (HY-13259)); 90 μM
(Lenalidomide (HY-A0003)) -
Incubation Time:24 h (this compound); 4 h (pre-incubation with inhibitors)
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Result:Had HPK1 degradation activity blocked by pre-treatment with MLN4924, lenalidomide, or MG-132.
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Cell Line:Jurkat cells
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Concentration:3, 10, 30, 100, 300 and 1000 nM
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Incubation Time:24 h
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Result:Selectively degraded HPK1 at 300 nM with low off-target risk.
Showed no obvious degradation activity for GCK, GLK, or HGK across tested concentrations.
| Species | Dose | Route | C0 | T1/2 | AUCinf | CL | Vss | Tmax | Cmax | F | AUC0-∞ | Vz |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 2 mg/kg | i.v. | / | 2.34 h | / | 35.9 mL/h/kg | / | / | / | / | 55748 ng·h/mL | 121.2 mL/kg |
| Mice[1] | 10 mg/kg | p.o. | / | 2.55 h | / | / | / | / | 14700 ng/mL | 20.7 % | 57823 ng·h/mL | / |
| Mice[1] | 2 mg/kg | i.v. | 1590 ng/mL | 1.17 h | 5559 ng·h/mL | 360 mL/h/kg | 659 mL/kg | / | / | / | / | / |
| Mice[1] | 10 mg/kg | p.o. | / | 3.44 h | 12071 ng·h/mL | / | / | 1.0 h | 3180 ng/mL | 43.7 % | / | / |
| Rat[1] | 2 mg/kg | i.v. | 3376 ng/mL | 2.82 h | 8223 ng·h/mL | 250 mL/h/kg | 834 mL/kg | / | / | / | / | / |
| Rat[1] | 1 mg/kg | p.o. | / | 5.15 h | 894 ng·h/mL | / | / | 3.17 h | 98.7 ng/mL | 19.2 % | / | / |
| Dog[1] | 1 mg/kg | i.v. | 794 ng/mL | 4.86 h | 996 ng·h/mL | 1022 mL/h/kg | 386 mL/kg | / | / | / | / | / |
| Dog[1] | 5 mg/kg | p.o. | / | 4.23 h | 796 ng·h/mL | / | / | 2.67 h | 111 ng/mL | 16.0 % | / | / |
DD205-291 (0.5 mg/kg; p.o.; single dose) achieves peak HPK1 degradation of 61.34% and peak phosphorylated SLP-76 degradation of 77.64% in mouse spleen, with activity declining over time[1].
DD205-291 (2-100 mg/kg; p.o.; daily; 14 days) is well-tolerated in SD rats at doses up to 100 mg/kg/day for 14 days, with a safety margin of 467 relative to its efficacy dose[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6J mice (female, 7-8 weeks old, subcutaneous implantation of 1 × 105 MC38 cells)[1]
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Dosage:0.02 mg/kg; 0.1 mg/kg; 0.5 mg/kg; 1 mg/kg (in combination with anti-PD1 5 mg/kg)
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Administration:p.o.; QD; BID; i.p.; BIW
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Result:Exerted dose-dependent antitumor effects.
Achieved a tumor growth inhibition (TGI) rate of 51.40% and a tumor weight inhibition (IR) rate of 42.22% at 0.5 mg/kg BID as monotherapy.
Achieved a TGI rate of 91.00% and an IR rate of 86.54% at 0.5 mg/kg BID in combination with anti-PD1.
Showed no significant changes in mouse body weight across all treatment groups.
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Animal Model:C57BL/6J mice[1]
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Dosage:0.5 mg/kg
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Administration:p.o.; single dose
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Result:Significantly degraded HPK1 protein in mouse spleen, reaching a peak degradation rate (D_max) of 61.34%.
Degraded phosphorylated SLP-76, with a peak D_max of 77.64% at 12 hours post-administration.
Showed degradation activity that gradually decreased over time.
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Animal Model:Sprague-Dawley (SD) rats (male and female, 6-7 weeks old)[1]
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Dosage:2 mg/kg; 30 mg/kg; 100 mg/kg
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Administration:p.o.; daily; 14 days
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Result:Showed systemic exposure that increased with dosage, with exposure increasing more than proportionally to dose.
Showed no gender differences in exposure or accumulation after repeated doses.
Caused no adverse effects on body weight, food intake, or clinical parameters across all doses.
Achieved a no-observed adverse effect level (NOAEL) of 100 mg/kg/day, resulting in a safety margin of 467 relative to the 0.8 mg/kg/day efficacy dose.
Chemical Information
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No. CAS 3047066-15-6
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Peso molecular 775.22
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Fòrmula C38H38ClF3N10O3
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SMILES
O=C(N1)N(C2=C(C=CC(C(N3CCC(CC3)CC4CCN(CC4)C5=CC=C(C=N5)C6=NC7=C(NC=C7C8=CN(N=C8)CC(F)(F)F)N=C6)=O)=C2)Cl)CCC1=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
DD205-291 Related Classifications
HY-168282 Related Classifications
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