SKI-178: A multitargeted inhibitor of sphingosine kinase and microtubule dynamics demonstrating therapeutic efficacy in acute myeloid leukemia models
Jeremy A Hengst1, Taryn E Dick1, Arati Sharma2, Kenichiro Doi3, Shailaja Hegde4, Su-Fern Tan5, Laura M Geffert1, Todd E Fox5, Arun K Sharma2, Dhimant Desai2, Shantu Amin2, Mark Kester5, Thomas P Loughran5, Robert F Paulson4, David F Claxton6, Hong-Gang Wang3, Jong K Yun1
1 Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA; The Jake Gittlen Laboratories for Cancer Research, The Pennsylvania State University College of Medicine, Hershey, PA, USA
2 Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA, USA
3 Department of Pediatrics, Penn State Hershey College of Medicine, Hershey, PA, USA
4 Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
5 University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA
6 Department of Hematology, Penn State Hershey Cancer Institute, Hershey, PA, USA
Jong K Yun
Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033-0850
Source of Support: None, Conflict of Interest: None
Aim: To further characterize the selectivity, mechanism of action, and therapeutic efficacy of the novel small molecule inhibitor, SKI-178.
Methods: We used the state-of-the-art cellular thermal shift assay technique to detect “direct target engagement” of proteins in intact cells. In vitro and in vivo assays, pharmacological assays, and multiple mouse models of acute myeloid leukemia (AML) were also used.
Results: Herein, we demonstrate that SKI-178 directly target engages both sphingosine kinase 1 and 2 (SphK1 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 induce 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 multitargeted 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 multitargeted anticancer therapeutic agent.