STF-1623 is a highly potent, selective, cell-impermeable non-covalent ENPP1 inhibitor, with IC50 values of 0.6 nM and 800 nM against human ENPP1 and ENPP3, respectively. STF-1623 inhibits the hydrolysis of extracellular cGAMP by ENPP1, elevates intratumoral cGAMP levels, and indirectly enhances local cGAS-STING signaling and anti-tumor immunity in tumors. STF-1623 exhibits target-dependent retention in ENPP1-highly expressing tumors, while it undergoes rapid clearance in systemic circulation, and can penetrate into the CSF and brain parenchyma. STF-1623 can be used in studies related to breast cancer, pancreatic cancer, colorectal cancer, glioblastoma, and tumor immunology [1] [2] [3] [4].
In Vivo, STF-1623 (compound 32) (300 mg/kg; subcutaneous injection; once daily; for 7 consecutive days) slows tumor growth and prolongs survival in mice with established E0771 triple-negative breast tumors[1]. STF-1623 (5-50 mg/kg; subcutaneous injection; once daily for 7 consecutive days) exerts effects in the orthotopic 4T1 breast cancer model: the 5 mg/kg dose delays primary tumor growth, while the 50 mg/kg dose improves the survival rate of mice[3]. STF-1623 (50-100 mg/kg; subcutaneous injection; once daily for 7 consecutive days) can cross the blood-brain barrier. When administered at a dose of 50 mg/kg in combination with temozolomide and ionizing radiation, it enables 62.5% of mice with intracranial GL261 glioblastoma to achieve complete tumor-free survival[3]. STF-1623 (50 mg/kg/day; subcutaneous injection; continuous administration; from day 0 to day 8) alone slows the growth of subcutaneous Panc02 tumors, and exerts a synergistic effect when combined with ionizing radiation, enhancing tumor growth inhibition and inducing disease stabilization or tumor regression in some mice[2]. STF-1623 (5-50 mg/kg; subcutaneous injection; once daily for 7 consecutive days, single-dose administration) increases intratumoral cGAMP levels and serum IFN−γ levels in an ENPP1-dependent manner[3]. STF-1623 (0.5-100 mg/kg; subcutaneous injection; once daily for 3 consecutive days, once daily for 7 consecutive days) combined with ionizing radiation reprograms the tumor immune microenvironment at doses ≥5 mg/kg, and completely inhibits the growth of Panc02 pancreatic tumors at doses of 50 or 100 mg/kg when combined with ionizing radiation[3].
In Vitro, STF-1623 exhibits IC50 values of 0.6 nM and 800 nM against purified human ENPP1 and ENPP3, respectively, and shows over 1000-fold selectivity for ENPP1[3]. STF-1623 inhibits the hydrolysis of cGAMP by purified mouse ENPP1 with a Ki,app of 16 nM, and suppresses extracellular cGAMP degradation in cells expressing human ENPP1 with an IC50 of 68 nM[2]. STF-1623 exhibits extremely low membrane permeability in artificial membranes and cell membranes, confirming that it cannot penetrate cells[2]. Incubation with STF-1623 (2 μM; 16 h) for 16 h shows no toxicity to primary human PBMC[2]. STF-1623 does not inhibit any of the 468 tested kinases, exhibiting extremely high kinome selectivity[2]. STF-1623 (2 μM; 24 h) selectively increases extracellular cGAMP concentrations, whereas it does not affect intracellular cGAMP levels in ENPP1-/- 293T cGAS cells expressing human ENPP1 after 24 h of incubation[2]. STF-1623 (2 μM; 16 h) does not alter the gene expression of cytokines (IFNB1, CXCL10) in primary human PBMCs induced by electroporated cGAMP, with an incubation duration of 16 h[2]. Compared with the PBS control, STF-1623 (0.6 mM; 6-24 h) does not significantly induce extracellular cGAMP, IFN-β mRNA, or IFN-β secretion in RAW264.7 cells[4].
References:
[1]. Carozza JA, et al. Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP. Cell chemical biology. 2020 Nov 19;27(11):1347-1358.e5.
[2]. Carozza JA, et al. Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity. Nature cancer. 2020 Feb;1(2):184-196.
[3]. Wang S, et al. ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy. Cell reports. Medicine. 2025 Sep 16;6(9):102336.
[4]. Sun G, et al. Soft-Drug-Inspired MnSTF Nano-Adjuvant for Safe and Synergistic cGAS-STING Activation in Tumor Immunotherapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2026 Feb;13(9):e15432.
In Vivo, STF-1623 (compound 32) (300 mg/kg; subcutaneous injection; once daily; for 7 consecutive days) slows tumor growth and prolongs survival in mice with established E0771 triple-negative breast tumors[1]. STF-1623 (5-50 mg/kg; subcutaneous injection; once daily for 7 consecutive days) exerts effects in the orthotopic 4T1 breast cancer model: the 5 mg/kg dose delays primary tumor growth, while the 50 mg/kg dose improves the survival rate of mice[3]. STF-1623 (50-100 mg/kg; subcutaneous injection; once daily for 7 consecutive days) can cross the blood-brain barrier. When administered at a dose of 50 mg/kg in combination with temozolomide and ionizing radiation, it enables 62.5% of mice with intracranial GL261 glioblastoma to achieve complete tumor-free survival[3]. STF-1623 (50 mg/kg/day; subcutaneous injection; continuous administration; from day 0 to day 8) alone slows the growth of subcutaneous Panc02 tumors, and exerts a synergistic effect when combined with ionizing radiation, enhancing tumor growth inhibition and inducing disease stabilization or tumor regression in some mice[2]. STF-1623 (5-50 mg/kg; subcutaneous injection; once daily for 7 consecutive days, single-dose administration) increases intratumoral cGAMP levels and serum IFN−γ levels in an ENPP1-dependent manner[3]. STF-1623 (0.5-100 mg/kg; subcutaneous injection; once daily for 3 consecutive days, once daily for 7 consecutive days) combined with ionizing radiation reprograms the tumor immune microenvironment at doses ≥5 mg/kg, and completely inhibits the growth of Panc02 pancreatic tumors at doses of 50 or 100 mg/kg when combined with ionizing radiation[3].
In Vitro, STF-1623 exhibits IC50 values of 0.6 nM and 800 nM against purified human ENPP1 and ENPP3, respectively, and shows over 1000-fold selectivity for ENPP1[3]. STF-1623 inhibits the hydrolysis of cGAMP by purified mouse ENPP1 with a Ki,app of 16 nM, and suppresses extracellular cGAMP degradation in cells expressing human ENPP1 with an IC50 of 68 nM[2]. STF-1623 exhibits extremely low membrane permeability in artificial membranes and cell membranes, confirming that it cannot penetrate cells[2]. Incubation with STF-1623 (2 μM; 16 h) for 16 h shows no toxicity to primary human PBMC[2]. STF-1623 does not inhibit any of the 468 tested kinases, exhibiting extremely high kinome selectivity[2]. STF-1623 (2 μM; 24 h) selectively increases extracellular cGAMP concentrations, whereas it does not affect intracellular cGAMP levels in ENPP1-/- 293T cGAS cells expressing human ENPP1 after 24 h of incubation[2]. STF-1623 (2 μM; 16 h) does not alter the gene expression of cytokines (IFNB1, CXCL10) in primary human PBMCs induced by electroporated cGAMP, with an incubation duration of 16 h[2]. Compared with the PBS control, STF-1623 (0.6 mM; 6-24 h) does not significantly induce extracellular cGAMP, IFN-β mRNA, or IFN-β secretion in RAW264.7 cells[4].
References:
[1]. Carozza JA, et al. Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP. Cell chemical biology. 2020 Nov 19;27(11):1347-1358.e5.
[2]. Carozza JA, et al. Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity. Nature cancer. 2020 Feb;1(2):184-196.
[3]. Wang S, et al. ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy. Cell reports. Medicine. 2025 Sep 16;6(9):102336.
[4]. Sun G, et al. Soft-Drug-Inspired MnSTF Nano-Adjuvant for Safe and Synergistic cGAS-STING Activation in Tumor Immunotherapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2026 Feb;13(9):e15432.