Development of SKI-349, a dual-targeted inhibitor of sphingosine kinase and microtubule polymerization

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Hengst, Jeremy A.¹  Hegde, Shailaja²  Paulson, Robert F.³  Yun, Jong K.¹ 

[1] Penn State Univ, Dept Pharmacol, Coll Med, 500 Univ Dr, Hershey, PA 17033 USA

[2] Univ Cincinnati, Hoxworth Blood Ctr, Childrens Hosp Med Ctr, Cincinnati, OH USA

[3] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA

关键词: Sphingosine kinase;    Sphingosine-1-phosphate;    Sphingosine kinase inhibitor;    Microtubule polymerization disruptor;    Dual-targeted inhibitor;   

DOI  :  10.1016/j.bmcl.2020.127453

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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