HDM2004
HDM2004 is a selective, orally active, blood-brain barrier-penetrant HPK1 inhibitor with an IC50 of 1.89 nM. HDM2004 exhibits anticancer activity against colon cancer. HDM2004 shows synergistic activity when combined with anti-PD-L1 in syngeneic mouse models. HDM2004 can be used for the research of colon cancer.
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- CAS No.: 2953016-30-1
- Formule: C28H35N7O
- Masse moléculaire:485.62
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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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HPK1 1.89 nM (IC50) |
HDM2004 potently inhibits recombinant HPK1 with an IC50 of 1.89 nM, and exhibits 31.88-fold selectivity over the highly homologous kinase GLK (GLK IC50 = 60.29 nM)[1].
HDM2004 enhances IL-2 secretion in human peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3/anti-CD28, with an EC50 of 38.9 nM[1].
HDM2004 exhibits excellent stability in mouse (t1/2 > 300 min) and human (t1/2 > 300 min) liver microsomes[1].
HDM2004 (1 μM) exhibits moderate kinome selectivity, with potent off-target inhibition of ROCK1 (94.04% inhibition, IC50 = 230.0 nM), VEGFR2 (91.39% inhibition, IC50 = 116.7 nM) and LCK (78.25% inhibition, IC50 = 300.1 nM); no significant inhibitory effect is observed on the remaining 44 safety-related targets[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | Cmax | Tmax | T1/2 | AUC0-24 | AUC0-t | AUC0-∞ | CL | Vss | Bioavailability | MRTlast | AUC0-last |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mice[1] | 2 mg/kg | i.v. | / | / | 1.25 h | / | / | 762 ng·h/mL | 42.9 mL/min/kg | 4.63 L/kg | / | / | / |
| Rat[1] | 10 mg/kg | p.o. | 486 ng/mL | 2.00 h | / | / | / | 1968 ng·h/mL | / | / | 52.0 % | / | / |
| Rat[1] | 1 mg/kg | i.v. | / | / | 8.00 h | / | / | 445 ng·h/mL | 25.8 mL/min/kg | 14.2 L/kg | / | / | / |
| Rat[1] | 5 mg/kg | p.o. | 83.5 ng/mL | 7.33 h | / | / | / | 1130 ng·h/mL | / | / | 55.4 % | / | / |
| Monkey[1] | 1 mg/kg | i.v. | / | / | 2.14 h | / | / | 413 ng·h/mL | 41.5 mL/min/kg | 7.48 L/kg | / | / | / |
| Monkey[1] | 20 mg/kg | p.o. | 306 ng/mL | 11.02 h | 11.02 h | / | / | 8011 ng·h/mL | / | / | 101 % | / | / |
| Monkey[1] | 60 mg/kg | p.o. | 537 ng/mL | 15.32 h | 15.32 h | / | / | 29254 ng·h/mL | / | / | 78.7 % | / | / |
| Mice[1] | 40 mg/kg | p.o. | 1693 ng/mL | 4.00 h | 3.67 h | 16949 ng·h/mL | 17455 ng·h/mL | 17483 ng·h/mL | / | / | / | / | / |
| Mice[1] | 60 mg/kg | p.o. | 2070 ng/mL | 6.00 h | 3.94 h | 32076 ng·h/mL | 33657 ng·h/mL | 33667 ng·h/mL | / | / | / | / | / |
| Mice[1] | 80 mg/kg | p.o. | 2333 ng/mL | 6.00 h | 4.52 h | 35831 ng·h/mL | 39755 ng·h/mL | 39843 ng·h/mL | / | / | / | / | / |
| Mice[1] | 100 mg/kg | p.o. | 2687 ng/mL | 4.00 h | 9.82 h | 35378 ng·h/mL | 42725 ng·h/mL | 44111 ng·h/mL | / | / | / | / | / |
| Rat[1] | 50 mg/kg | p.o. | 1076 (Plasma) ng/mL | 8 (Plasma) h | / | / | / | / | / | / | / | 10.64 (Plasma) h | 17554 (Plasma) ng·h/mL |
HDM2004 (20-60 mg/kg; p.o.; QD; 2 weeks) exhibits synergistic antitumor activity when combined with anti-mouse PD-L1 in the MC38 colon carcinoma syngeneic mouse model, with a maximum TGI rate of 77.05% at the 60 mg/kg oral daily dose plus anti-mouse PD-L1[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 (female, 6-8 weeks old, inoculated subcutaneously with MC38 colon carcinoma cells)[1]
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Dosage:20 mg/kg; 40 mg/kg; 60 mg/kg
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Administration:p.o.; QD; 2 weeks
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Result:Reduced mean tumor volume to 1745.74 ± 293.04 mm3 and achieved a TGI rate of 14.25% at 20 mg/kg on Day 20.
Reduced mean tumor volume to 1218.76 ± 228.78 mm3 and achieved a TGI rate of 40.07% at 40 mg/kg on Day 20.
Reduced mean tumor volume to 973.24 ± 103.47 mm3 and achieved a TGI rate of 52.10% at 60 mg/kg on Day 20.
Caused no significant body weight loss in treated mice.
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Animal Model:C57BL/6J (female, 6-8 weeks old, inoculated subcutaneously with MC38 colon carcinoma cells)[1]
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Dosage:20 mg/kg (in combination with anti-mouse PD-L1); 40 mg/kg (in combination with anti-mouse PD-L1); 60 mg/kg (in combination with anti-mouse PD-L1)
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Administration:p.o.; QD; 2 weeks
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Result:Reduced mean tumor volume to 760.85 ± 160.55 mm3 and achieved a TGI rate of 62.62% at 20 mg/kg in combination with anti-mouse PD-L1 on Day 20.
Reduced mean tumor volume to 537.55 ± 70.74 mm3 and achieved a TGI rate of 73.56% at 40 mg/kg in combination with anti-mouse PD-L1 on Day 20.
Reduced mean tumor volume to 467.12 ± 105.04 mm3 and achieved a TGI rate of 77.05% at 60 mg/kg in combination with anti-mouse PD-L1 on Day 20.
Caused no significant body weight loss in treated mice.
Chemical Information
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CAS No. 2953016-30-1
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Masse moléculaire 485.62
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Formule C28H35N7O
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SMILES
CCN(CC1)CCC1N(N=C2)C=C2C3=CNC4=C3N=C(C5=CC=C(N6C[C@@H](C)O[C@H](C)C6)C=C5)C=N4
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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)
HDM2004 Related Classifications
HY-181932 Related Classifications
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