INCB191358
INCB191358 is a selective and orally active inhibitor of diacylglycerol kinase α/ζ/ι (DGKα/ζ/ι ) with IC50 values of 0.12, 0.36 and 0.36 nM. INCB191358 induces antigen-dependent T-cell activation, induces IL-2 production and enhances antitumor efficacy in combination with PD-1 blockade. INCB191358 can be used for the research of cancer, such as colon carcinoma.
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- CAS. Nr.: 3111036-70-2
- Formel: C25H30F3N5O3
- Molecular Weight:505.53
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
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Help & FAQs
Biologische Aktivität
Beschreibung
IC50 & Target
[1]|
DGKα 0.12 nM (IC50) |
DGKζ 0.36 nM (IC50) |
DGKι 0.36 nM (IC50) |
DGKβ 8.8 nM (IC50) |
DGKγ 21 nM (IC50) |
IL-2 |
In Vitro
INCB191358 (Compound 52) potently inhibits DGKα (IC50 = 0.12 nM) and DGKζ/ι (IC50 = 0.36 nM) in purified enzyme assays, with high selectivity over off-target Type I DGK isoforms DGKβ and DGKγ[1].
INCB191358 induces IL-2 production in Jurkat T cells with an EC50 of 11 nM[1].
INCB191358 induces IL-2 production in human whole blood with an EC50 of 22 nM[1].
INCB191358 demonstrates balanced in vitro ADME properties, including moderate intrinsic clearance and high Caco-2 permeability[1].
INCB191358 shows no significant cytotoxicity in HEK293 cells, with an IC50 >27 μM[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
Parmacokinetics
In Vivo
INCB191358 (0.3-3 mg/kg; p.o.) enhances antitumor efficacy in combination with anti-PD-1 blockade in MC38 tumor-bearing mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:OT-I transgenic mice (female)[1]
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Dosage:0.1 mg/kg; 0.3 mg/kg; 1 mg/kg
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Administration:p.o.; companied with SINFEKL (0.025 μg)
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Result:Induced a dose-dependent increase in CD69+ CD8+ T cells, with the greatest activation observed at 1 mg/kg.
Exceeded the whole blood EC50 (22 nM) at 4 h but fell below the EC50 by 24 h at 1 mg/kg dose.
Resulted in plasma concentrations below the whole blood EC50 at both 4 h and 24 h time points and only modest at 0.1 and 0.3 mg/kg doses.
Did not induce significant T-cell activation when administered as a single agent at 1 mg/kg.
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Animal Model:C57BL/6 mice (female; MC38 syngeneic tumor implanted, treatment initiated day 7 post-implantation)[1]
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Dosage:0.3 mg/kg; 1 mg/kg; 3 mg/kg
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Administration:p.o.; in combination with anti-PD-1
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Result:Produced tumor growth inhibition (TGI) of 47% when administered in combination with anti-PD-1 antibody at 0.3 mg/kg.
Achieved significantly greater inhibition with TGI of 78% and 81% when administered in combination with anti-PD-1 antibody at 1 mg/kg and 3 mg/kg doses, respectively.
Showed synergistic activity via Bliss independence analysis for the 1 mg/kg (+19% excess-over-Bliss) and 3 mg/kg (+8.6% excess-over-Bliss) combination groups.
Exhibited minimal antitumor activity with TGI = 19% as a single agent at 1 mg/kg.
Achieved TGI of 48% as a single agent at 3 mg/kg.
Chemical Information
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CAS. Nr. 3111036-70-2
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Molecular Weight 505.53
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Formel C25H30F3N5O3
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SMILES
CC1=NC2=C(N1C[C@@H]3CCCO3)N(C(N=C2N4CC[C@@H](C[C@@H]4C)OC5=CC=C(C=C5)C(F)(F)F)=O)C
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Protokoll
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Patient-Derived Xenograft (PDX)
Patient-derived xenograft (PDX) models are generated by engrafting primary human tumor tissue directly into immunodeficient mice, allowing in vivo propagation of patient tumor biology without initial in vitro adaptation. These models are used to preserve key histopathological and molecular characteristics of the original tumor and enable assessment of tumor growth dynamics and therapeutic response in a living organism. The biological readout is tumor engraftment and subsequent growth in the murine host, which reflects the ability of human tumor cells to survive, vascularize, and expand in an immunocompromised microenvironment.
Reinheit & Dokumentation
Verweise
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
INCB191358 Related Classifications
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