SKI II (hydrochloride)

SKI-II hydrochloride is an orally active dual-target inhibitor of SphK1/2 and DES1, with K_i values of 16 µM and 0.3 µM against SphK1 and DES1, respectively. SKI-II hydrochloride activates the PERK-Nrf2 antioxidant pathway by stabilizing Nrf2, and synergizes with Temozolomide (HY-17364) to induce oxidative/endoplasmic reticulum stress and cancer cell death under hypoxic conditions. SKI-II hydrochloride inhibits SphK activity, promotes ceramide accumulation and apoptosis, and synergizes with Cisplatin (HY-17394) to reverse drug resistance via the ras/MAPK pathway in vivo. SKI-II hydrochloride reduces measles virus replication by inhibiting mTORC1 activity. SKI-II hydrochloride binds to VCP to induce M1 polarization, enhances host tolerance to Staphylococcus aureus infection, and exerts radioprotective effects through Nrf2 activation and accelerated DNA repair. SKI-II hydrochloride can be used in research related to glioblastoma, acute myeloid leukemia, gastric cancer, measles virus infection, Staphylococcus aureus infection, and acute radiation syndrome^{[1][2][3][4][5][6][7][8]}. In Vitro:SKI II (1.25 μM; 48 h) hydrochloride reverses the resistance of human gastric cancer SGC7901/DDP cells to Cisplatin (HY-17394)^[1].
SKI II (5-10 μM; 48 h) hydrochloride downregulates the expressions of P-gp, MRP1, p-ERK and p-JNK in human gastric cancer cell line SGC7901/DDP, and the effect is more significant when used in combination with Cisplatin^[1].
SKI II (5-10 μM; 48 h) hydrochloride reduces the protein expression levels of P-gp, MRP1, p-ERK and p-JNK in human gastric cancer cell line SGC7901/DDP, and the inhibitory effect is enhanced when used in combination with Cisplatin^[1].
SKI II (5-10 μM; 48 h) hydrochloride downregulates the mRNA expression of MRP1 and GST in human gastric cancer cell line SGC7901/DDP, and the inhibitory effect is enhanced when used in combination with Cisplatin^[1].
SKI II (5-10 μM; 48 h) hydrochloride reduces the intracellular GSH level in human gastric cancer cell line SGC7901/DDP, and its combination with cisplatin further decreases GSH level and inhibits GST activity^[1].
SKI II (0.33-5.32 μM; 5 days) hydrochloride inhibits the growth of human glioblastoma NCH82 cells, with an ED₅₀ of approximately 1.3 μM under both normoxic and hypoxic conditions; it also exerts a synergistic effect with Temozolomide (HY-17364)^[3].
SKI II (2.66 μM; 4 weeks) hydrochloride impairs the self-renewal capacity of human DMSO-1080 and temozolomide (TMZ)-resistant TMZ-1080 glioblastoma stem-like cells under both normoxic and hypoxic conditions, with an efficacy comparable to that of combined treatment with temozolomide, and its effect on TMZ-resistant GSCs is particularly pronounced under hypoxic conditions^[3].
SKI II (2.66 μM; 5 days) hydrochloride impairs the invasive capacity of human mesenchymal glioblastoma U3054MG spheroids under both normoxic and hypoxic conditions^[3].
SKI II (100 nM) hydrochloride exerts radioprotective effects by promoting the proliferation of Raw 264.7 mouse macrophages and INT-407 human intestinal epithelial cells^[6].
SKI II (100 nM; 2 h pretreatment before IR, 7-10 days) hydrochloride enhances the clonogenic radioresistance of Raw 264.7 mouse macrophages and INT-407 human intestinal epithelial cells^[6].
SKI II (100 nM; 2 h pretreatment prior to 2 Gy IR, 60 min-72 h post-IR) hydrochloride reduces ionizing radiation (IR)-induced DNA double-strand breaks and cytogenetic damage in Raw 264.7 mouse macrophages, as evidenced by decreased γ-H2AX foci and reduced micronucleus formation rate^[6].
SKI II (5 μM; 6-24 h) hydrochloride reduces the phosphorylation level of eIF4E in uninfected primary human peripheral blood lymphocytes (PBL), inhibits the increase in total MNK1 expression, and shows a tendency to decrease the phosphorylation level of rpS6^[2].
SKI II (100 nM-5000 nM; 48-72 h) hydrochloride shows no toxicity in Raw 264.7 mouse macrophages and INT-407 human intestinal epithelial cells; concentration-dependent cytotoxicity is observed only in Raw 264.7 cells at concentrations of 700 nM and higher^[6].
SKI II (5 μM; 3-24 h) hydrochloride reduces the expression levels of total rpS6, phosphorylated rpS6, phosphorylated eIF4E, and total IKK in primary human peripheral blood lymphocytes (PBL) infected with measles virus (MV)^[2].
SKI II (1-5 μM; 2-3 days) hydrochloride reduces the replication level of MV in primary human peripheral blood lymphocytes (PBLs) by approximately one log order upon infection^[2].
SKI II (5 μM; 24 h) hydrochloride reduces the expression of GFP and MV-H proteins in primary human peripheral blood lymphocytes (PBL) infected with measles virus (MV), while the expression of MV-N protein remains unchanged^[2].
SKI II (2.66 μM; 3-5 days) hydrochloride induces approximately 30% cell death in human glioblastoma NCH82 cells under normoxic conditions; when combined with Temozolomide, it further increases the proportion of cell death by approximately 30%, and its cell death-inducing effect under hypoxic conditions is significantly stronger than that of Temozolomide used alone^[3].
SKI II (2.66 μM; 48 h) hydrochloride, either used alone or in combination with Temozolomide, acts on human glioblastoma NCH82 cells under both normoxic and hypoxic conditions, reduces the levels of ceramide and its metabolites, and downregulates the ceramide/dihydrosphingosine ratio^[3].
SKI II (10 nM) hydrochloride binds to the ATPase domain of human VCP, as well as Caenorhabditis elegans CDC-48.1 and CDC-48.2, with nanomolar-level binding affinity, and acts as a competitive inhibitor of ATP binding^[5].
SKI II (4 μg/mL; 2-24 h) hydrochloride activates Nrf2-mediated oxidative stress responses in mouse RAW264.7 macrophages via a PERK-dependent pathway, reduces infection-induced reactive oxygen species levels, and decreases intracellular Staphylococcus aureus loads^[5].
SKI II (4 μg/mL; 2-24 h) hydrochloride promotes M1 polarization of mouse RAW264.7 macrophages, enhances their sensitivity to subsequent LPS stimulation, and induces a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis^[5].
SKI II (8-32 μg/mL; 8 h-5 days) hydrochloride activates the SKN-1/Nrf2 pathway in Caenorhabditis elegans in a CDC-48-dependent manner, reduces infection-induced reactive oxygen species levels, and improves host survival during Staphylococcus aureus infection via a host-directed mechanism^[5].
SKI II (1 nM-1000 nM; 1 h-24 h) hydrochloride upregulates Nrf2 protein expression in a concentration- and time-dependent manner in Raw 264.7 mouse macrophages and INT-407 human intestinal epithelial cells^[6].
SKI II (100 nM; 2 h pretreatment prior to 2 Gy IR, 4 h-36 h post-IR) hydrochloride alleviates IR-induced oxidative stress in Raw 264.7 mouse macrophages by reducing ROS levels, restoring MMP, enhancing antioxidant enzyme activity and GSH levels, and upregulating the Nrf2 signaling pathway^[6].
SKI II (100 nM; pretreated for 2 h before 2 Gy irradiation and treated for 24 h after irradiation) hydrochloride reduces irradiation-induced apoptosis, decreases caspase-3/7 activity, and regulates the expression of pro-apoptotic and anti-apoptotic proteins in Raw 264.7 mouse macrophages^[6]. In Vivo:SKI II (0.3 mg/kg; i.p.; single administration; 48 h exposure) hydrochloride alone reduces the expressions of P-gp, MRP1, p-ERK, p-JNK, GSH and GST in tumor tissues of subcutaneous gastric cancer nude mouse models, and enhances the effects of Cisplatin (HY-17394) on these targets^[1].

Hydrochloride of SKI II (10-50 mg/kg; intraperitoneal injection; once daily; for 7 consecutive days) dose-dependently inhibits the growth of U937 acute myeloid leukemia xenografts in SCID/beige mice without inducing obvious toxicity^[4].
Treatment with SKI II (50.0 mg/kg, i.p.; 100 mg/kg, p.o.) reduces tumor growth in mice bearing solid tumor models^[7].
SKI II (4-32 μg/mL; liquid incubation; 8-24 hours; liquid infection assay; 5 days) hydrochloride activates the SKN-1/Nrf2 pathway in Caenorhabditis elegans, thereby reducing pathogenic ROS, restoring physiological functions, and improving survival rate during Staphylococcus aureus infection^[5].
Hydrochloride form of SKI II (0.1 mg/kg; i.p.; administered once before irradiation and once every 24 h after irradiation, for a total of 3 doses) exerts radioprotective effects on C57BL/6 mice exposed to lethal ionizing radiation^[6].
Hydrochloride form of SKI II (0.1 mg/kg; i.p.; administered once before irradiation, followed by once every 24 h post-irradiation until 72 h post-irradiation) protects C57BL/6 mice against radiation-induced cytopenia by reducing initial cytopenia and promoting hematopoietic recovery^[6].