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 ^[1].

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].

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].

References:
[1]. Wei B, et al. Discovery of INCB191358: A Potent and Selective DGKα/ζ Dual Inhibitor. J Med Chem. 2026;69(9):10545-10578.