2. Metabolic Enzyme/Protease Immunology/Inflammation
  3. DGK Interleukin Related
  4. 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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INCB191358

INCB191358 Chemical Structure

CAS No. : 3111036-70-2

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INCB191358 Related Antibodies

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Description

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[1].

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.

INCB191358 Related Antibodies
Parmacokinetics
Species Dose Route T1/2 Vdss AUC Cmax F
Rat[1] 1 mg/kg p.o. / / 661 nM·h 79 nM 14 %
Cynomolgus Monkey[1] 0.25 mg/kg p.o. / / 818 nM·h 63 nM 57 %
Rat[1] 0.25 mg/kg i.v. 2.7 h 1.3 L/kg / / /
Cynomolgus Monkey[1] 0.05 mg/kg i.v. 5 h 2 L/kg / / /
In Vivo

INCB191358 (Compound 52) (0.1-1 mg/kg; p.o.; single dose) induces dose-dependent antigen-specific CD8+ T-cell activation in OT-I mice companied with SINFEKL[1].
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.

Animal Model: OT-I transgenic mice (female)[1]
Dosage: 0.1 mg/kg; 0.3 mg/kg; 1 mg/kg
Administration: p.o.; companied with SINFEKL (0.025 μg)
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.
Animal Model: C57BL/6 mice (female; MC38 syngeneic tumor implanted, treatment initiated day 7 post-implantation)[1]
Dosage: 0.3 mg/kg; 1 mg/kg; 3 mg/kg
Administration: p.o.; in combination with anti-PD-1
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.
Molecular Weight

505.53

Formula

C25H30F3N5O3
CAS No.
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
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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INCB191358 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

INCB1913583111036-70-2INCB 191358INCB-191358DGKInterleukin RelatedDiacylglycerol kinaseILDGKζdiacylglycerol kinase ζMC38 tumor-bearing miceHEK293 cellsT-cell activationdiacylglycerol kinase αT-cell receptor signalingcolon carcinomaDGKαJurkat T cellsInhibitorinhibitorinhibit

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INCB191358
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