Alcudacigib TFA (Synonyms: DGKζ-IN-1 TFA)

Alcudacigib (ASP1570; DGKζ-IN-1) TFA is an orally active diacylglycerol kinase ζ ( DGKζ ) inhibitor, with an IC₅₀ of 4.7 nM against human DGKζ and an IC₅₀ of 3.0 nM against mouse DGKζ. Alcudacigib TFA selectively inhibits the kinase activity of DGKζ and induces proteasome-dependent degradation of DGKζ protein. Alcudacigib TFA enhances the anti-tumor functions of T cells and NK cells. Alcudacigib TFA can be used for the research of advanced/metastatic solid tumors ^{[1] [2]}.

In Vivo, Alcudacigib (0.1-10 mg/kg; p.o.; once daily or twice daily for 10 consecutive days) TFA dose-dependently inhibits the growth of MC38 colon adenocarcinoma in mice^[2]. Alcudacigib (0.1-3 mg/kg; p.o.; once daily or twice daily for 9-10 consecutive days) TFA inhibits the growth of CPI-resistant B16F1 melanoma in female C57BL/6J mice^[2]. Alcudacigib (3 mg/kg; p.o.; once daily for 10 consecutive days) TFA exerted its antitumor effect against B16F10 melanoma in female C57BL/6J mice in a CD8+T cell-dependent manner^[2]. Alcudacigib (3 mg/kg; p.o.; single administration) TFA enhances the expression of T cell activation markers (CD25 and CD69) in splenic CD4+ and CD8+ T cells of healthy female C57BL/6J mice^[2].

In Vitro, Alcudacigib (0.1 μM; 5-30 min) TFA enhances DAG-mediated ERK phosphorylation in DX5+ NK cells isolated from the spleens of wild-type mice stimulated with anti-NK1.1^[1]. Alcudacigib (0.001-1 μM; 5 h) TFA dose-dependently enhances IFN-γ production and degranulation in CD4/8-DX5+NKp46+ NK cells from wild-type mouse spleens stimulated with anti-NK1.1^[1]. Alcudacigib (0.1-1000 nM; 5.5-24.5 h) TFA degrades the DGKζ protein in Jurkat and B16F1 cells through a proteasome-dependent mechanism^[2]. Alcudacigib (0.0003-1 μM; 30 min) TFA enhances the downstream signaling pathway of DAG in TCR-stimulated Jurkat cells, which is evidenced by statistically significant increases in the phosphorylation levels of PKD and ERK1/2^[2]. Alcudacigib (0.0003-1 μM; 24 h) TFA enhances IL-2 production in TCR-stimulated Jurkat cells^[2]. Alcudacigib (0.0001-1 μM; 3 days) TFA enhances the proliferation, IL-2 production and IFN-γ production of human primary CD8+ T cells activated via TCR^[2]. Alcudacigib (0.0001-1 μM; 3 days) TFA restores and enhances the activation of primary human CD8+ T cells (including cell viability, IL-2 production, and IFN-γ production) that is inhibited by TGF-β1, PGE2 or AMP^[2]. Alcudacigib (0.0001-1 μM; 3 days) TFA enhances proliferation, IL-2 production and IFN-γ production of primary mouse CD8+ T cells stimulated by TCR^[2]. Alcudacigib (0.0003-3 μM; 24 h) TFA completely reverses PD-1-mediated T cell suppression and partially reverses CTLA-4- and TIGIT-mediated T cell suppression in cellular assays^[2].

References:
[1]. Okumura M, et al. The diacylglycerol kinase ζ inhibitor ASP1570 augments natural killer cell function. Int Immunopharmacol. 2023;125(Pt A):111145.
[2]. Ikeda O, et al. Enhanced Antitumor Immunity by ASP1570, a Novel Diacylglycerol Kinase ζ Inhibitor, Offers a Potential Novel Immunotherapy for Treating Cancer. Mol Cancer Ther. 2025;24(6):884-895.