Development of SKI-349, a dual-targeted inhibitor of sphingosine kinase and microtubule polymerization. Issue 20 (15th October 2020)

• Record Type: Journal Article
• Authors: Hengst, Jeremy A.; Hegde, Shailaja; Paulson, Robert F.; Yun, Jong K.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 20(2020)
• Publication Date: 2020-10-15
• Subjects: Sphingosine kinase -- Sphingosine-1-phosphate -- Sphingosine kinase inhibitor -- Microtubule polymerization disruptor -- Dual-targeted inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127453
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Herein we report the refinement of a bifunctional sphingosine kinase inhibitor/microtubule disruptor chemotype and identification of a lead compound, SKI-349. Abstract: Our sphingosine kinase inhibitor (SKI) optimization studies originated with the optimization of the SKI-I chemotype by replacement of the substituted benzyl rings with substituted phenyl rings giving rise to the discovery of SKI-178. We have recently reported that SKI-178 is a dual-targeted inhibitor of both sphingosine kinase isoforms (SphK1/2) and a microtubule disrupting agent (MDA). In mechanism-of-action studies, we have shown that these two separate actions synergize to induce cancer cell death in acute myeloid leukemia (AML) cell and animal models. Owning to the effectiveness of SKI-178, we sought to further refine the chemotype while maintaining "on-target" SKI and MDA activities. Herein, we modified the "linker region" between the substituted phenyl rings of SKI-178 through a structure guided approach. These studies have yielded the discovery of an SKI-178 congener, SKI-349, with log-fold enhancements in both SphK inhibition and cytotoxic potency. Importantly, SKI-349 also demonstrates log-fold improvements in therapeutic efficacy in a retro -viral transduction model of MLL-AF9 AML as compared to previous studies with SKI-178. Together, our results strengthen the hypothesis that simultaneous targeting of the sphingosine kinases (SphK1/2) and the induction of mitotic spindle assembly checkpoint arrest, via microtubule disruption, might be an effective therapeutic strategy for hematological malignancies including AML.