Development of SKI-349, a Dual-Targeted Inhibitor of Sphingosine Kinase and Microtubule Polymerization

Autor: Shailaja Hegde, Jong K. Yun, Robert F. Paulson, Jeremy A. Hengst
Jazyk: angličtina
Rok vydání: 2020
Předmět:
animal structures
Cell Survival
Clinical Biochemistry
Sphingosine kinase
Pharmaceutical Science
Antineoplastic Agents
01 natural sciences
Biochemistry
Microtubules
Article
Microtubule polymerization
Polymerization
chemistry.chemical_compound
Structure-Activity Relationship
Drug Development
Cell Line
Tumor
Drug Discovery
Humans
Sphingosine-1-phosphate
Enzyme Inhibitors
Molecular Biology
Cell Proliferation
Sphingosine
Dose-Response Relationship
Drug
Molecular Structure
010405 organic chemistry
Kinase
Organic Chemistry
Myeloid leukemia
musculoskeletal system
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Phosphotransferases (Alcohol Group Acceptor)
chemistry
Mitotic spindle assembly checkpoint
Cancer cell
Cancer research
Molecular Medicine
Drug Screening Assays
Antitumor
human activities
Zdroj: Bioorg Med Chem Lett
Popis: 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.
Databáze: OpenAIRE
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