SKI 178 is a non-selective inhibitor of Sphingosine Kinases (SphK1 and SphK2). SKI 178 competitively binds to the Sph binding site in SphK1, effectively inhibiting Sphingosine-1-Phosphate (S1P) production while inducing intracellular Ceramide (Cer) accumulation and promoting cancer cell apoptosis. SKI 178 exhibits potent cytotoxicity against various cancer cell lines and shows potential in the treatment of solid tumors and hematologic malignancies. SKI 178 also has a microtubule network disrupting effect in vitro and in intact cells[1].
In vitro, SKI 178 (0.08-10µM; 16h) dose‑dependently stabilizes both SphK1 and SphK2 proteins in HEK293 stably overexpresses His6X-SphK1 and His6X-SphK2, with an IC₅₀ of 400-800nM for both[1]. SKI 178 (5µM; 18h) destabilized microtubule polymerization and reduced the rate of tubulin polymerization in HL‑60 cells[1]. SKI 178 (5-25µM; 48-96h) inhibited the viability of primary human prostate cancer cells (PCan1) in a concentration‑ and time‑dependent manner[2]. SKI 178 (5–25µM) dose‑dependently inhibited PCan1 cell proliferation at 48h and cell migration at 16h[2]. SKI 178 (10µM; 72h) showed no significant inhibition of cell viability in RWPE‑1 cells and primary prostate epithelial cells[2]. SKI 178 (10μM; 36h) induced cell cycle arrest and apoptosis in prostatecancer cell[2]. SKI 178 (10µM; 24h) impaired mitochondrial functions in pCan1 primary cells, causing mitochondrial depolarization, ROS production, oxidative injuryand ATP reduction[2].
In vivo, treatment with SKI 178 (20mg/kg; tail vein i.v.; every other day for 1 or 3 weeks) significantly reduced white blood cell counts in the bone marrow of MLL‑AF9 mice, with no observed weight loss or overt toxicity[1]. Retro‑orbital injection of SKI 178 at 20, 10, and 5mg/kg every other day for 1 week reduced white blood cell counts in MLL‑AF9 mice in a dose‑dependent manner[1]. SKI 178 (25mg/kg/d; i.p.; 18d) effectively suppresses PC‑3 xenograft tumor growth in nude mice, concomitantly inhibiting SphK activity and impairing mitochondrial function in tumor tissues, while promoting JNK activation and suppressing the Akt–mTOR pathway[2].
References:
[1] Hengst, Jeremy A et al. “SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models.” Cancer translational medicine vol. 3,4 (2017): 109-121.
[2] Jin L, Zhu J, Yao L, Shen G, Xue BX, Tao W. Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth. Cell Death Dis. 2023;14(8):537. Published 2023 Aug 21.