SKI-178: A multitargeted inhibitor of sphingosine kinase and microtubule dynamics demonstrating therapeutic efficacy in acute myeloid leukemia models

Abstract

Aim To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178. Methods Using the state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect “direct target engagement” of proteins intact cells, in vitro and in vivo assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML). Results Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2. We also present evidence that, in addition to its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a microtubule network disrupting agent both in vitro and in intact cells. Interestingly, we separately demonstrate that simultaneous SphK inhibition and microtubule disruption synergistically induces apoptosis in AML cell lines. Furthermore, we demonstrate that SKI-178 is well tolerated in normal healthy mice. Most importantly, we demonstrate that SKI-178 has therapeutic efficacy in several mouse models of AML. Conclusion SKI-178 is a multi-targeted agent that functions both as an inhibitor of the SphKs as well as a disruptor of the microtubule network. SKI-178 induced apoptosis arises from a synergistic interaction of these two activities. SKI-178 is safe and effective in mouse models of AML, supporting its further development as a multi-targeted anti-cancer therapeutic agent.

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

“…Both SPHK1/2 alone and SPHK1/2 KD together with ISO treatment strongly reduced the expression of α/β-tubulin and pERK, in addition to increasing cleaved PARP. A previous study also revealed similar results, in which a multitargeted SPHK inhibitor participated in microtubule dynamic disturbances [24]. As these target genes are critically involved in the proliferation and survival of cancer cells, alteration of these genes by SPHK1/2 could be responsible for anti-cancer activity.…”

“…Sphingosine modulators were also reported to be linked with tubulin disruption and have subsequent anti-cancer effects. Previous reports have suggested that SKI-178, being a sphingosine kinase inhibitor, functioned as a microtubule network-disrupting agent, showing strong anti-cancer potency by inducing acute myeloid leukemia cell death [24]. ISO dramatically lowered the expression and activity of SPHKs.…”

“…ISO dramatically lowered the expression and activity of SPHKs. Additionally, docking studies with SK1 protein were conducted to validate the interaction of ISO and Rsv with SK1 [24,66]. The docking results suggest that both compounds have the potential to interact with SK1 protein, but their binding potential is weaker than that of the known SK1 inhibitor.…”

Intimate Relations—Mitochondria and Ageing

“…Many studies have indicated that these highly regulated processes of fission and fusion, (generally termed mitochondrial dynamics) are essential for the health of the cell and their disruption experimentally has profound consequences, while altered morphology of the network towards either a highly fragmented or a hyperfused morphology is associated with disease and ageing. In addition, there are mitochondrial morphologies that do not fit this simple hyperfused/hyper fragmented axis, which nevertheless arise from disturbances to the fission/fusion process and which are associated with cellular dysfunction, such as the granular phenotype described by Hengst et al [ 370 ]. We will briefly review the major molecular components of the mitochondrial dynamics system to provide context for the discussion that follows.…”

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

“…Two other SphK1 inhibitors, SKI-178 and PF-543, also occupy the substrate-binding site of SphK and thus prevent the phosphorylation of sphingosine (Hengst et al, 2017; Schnute et al, 2012; Wang, Knapp, Pyne, Pyne, & Elkins, 2014). …”