TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis
Science Translational Medicine • 22 Oct 2014 • Vol 6, Issue 259 • p. 259ra145 • DOI: 10.1126/scitranslmed.3010277
Anticancer Drug Coming Out on TOPK
TOPK (T–lymphokine-activated killer cell–originated protein kinase) is a protein that is found in a wide range of human cancers and is believed to work as an oncogene, promoting tumor growth. Now, Matsuo et al. have developed a drug that can inhibit TOPK and can be delivered by multiple routes. The oral form of this drug was well tolerated by mice and allowed convenient and effective treatment. An intravenous form was even more effective, and providing it as a liposomal formulation was successful in eliminating hematological side effects while simultaneously promoting complete regression of the tumors. These results suggest that the TOPK inhibitor may be a viable anticancer agent, although human trials will be required before this drug can be used in the clinic.
Abstract
TOPK (T–lymphokine-activated killer cell–originated protein kinase) is highly and frequently transactivated in various cancer tissues, including lung and triple-negative breast cancers, and plays an indispensable role in the mitosis of cancer cells. We report the development of a potent TOPK inhibitor, OTS964 {(R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c]quinolin-4(5H)-one}, which inhibits TOPK kinase activity with high affinity and selectivity. Similar to the knockdown effect of TOPK small interfering RNAs (siRNAs), this inhibitor causes a cytokinesis defect and the subsequent apoptosis of cancer cells in vitro as well as in xenograft models of human lung cancer. Although administration of the free compound induced hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively caused complete regression of transplanted tumors without showing any adverse reactions in mice. Our results suggest that the inhibition of TOPK activity may be a viable therapeutic option for the treatment of various human cancers.
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Supplementary Material
Summary
Materials and Methods
Fig. S1. Correlation between TOPK expression and clinical outcome.
Fig. S2. Cell-based antiproliferative assay for OTS514.
Fig. S3. LU-99 lung cancer xenograft model treated with intravenous administration of free OTS514.
Fig. S4. Cell-based antiproliferative assay for OTS964.
Fig. S5. Expression of Src family kinases in cancer cell lines.
Fig. S6. Inhibition of TOPK activity by OTS964 treatment.
Fig. S7. Enhancement of HSC differentiation to megakaryocytes by TOPK inhibitors.
Fig. S8. Histological examination of liver toxicity with liposomal OTS964.
Fig. S9. Cytokinetic defects in LU-99 cells after administration of liposomal OTS964.
Fig. S10. Effects of liposomal OTS964 on proliferation and death of cancer cells.
Fig. S11. Morphological changes and apoptosis of cancer cells after treatment with liposomal OTS964.
Fig. S12. LU-99 xenograft model treated by oral administration of free OTS964.
Fig. S13. Immunohistochemical staining of LU-99 tumor sections after oral administration of free OTS964.
Table S1. Kinase profile analysis of OTS514 and OTS964.
Table S2. Original data for composite figures from in vitro and in vivo experiments including P values (provided as a separate Excel file).
Video S1. Cytokinetic defect and apoptosis of T47D cells caused by OTS964 treatment.
Video S2. Normal proliferation of T47D cells.
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Information & Authors
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Published In
Science Translational Medicine
Volume 6 | Issue 259
October 2014
October 2014
Copyright
Copyright © 2014, American Association for the Advancement of Science.
Submission history
Received: 6 August 2014
Accepted: 23 September 2014
Acknowledgments
We thank K. Adachi, K. Toyota, and M. Mutonga for technical support, T. Katagiri for helpful discussion, and W. Stock for providing human HSCs. Funding: This work was supported in part by the Innovation Promotion Program of the New Energy and Industrial Technology Development Organization of Japan and OncoTherapy Science Inc. Author contributions: Y.N. planned and supervised the entire project. Y.M. contributed to the planning of the discovery research and the compound design. J.-H.P. and Y.N. performed functional study in tumor and analyzed data. T.M., S.Y., and S.H. contributed to most in vitro and in vivo experiments using TOPK inhibitors. H.A. performed experiments using HSCs. Y.M., J.-H.P., and Y.N. wrote the manuscript. Competing interests: Y.M., T.M., S.Y., and S.H. are employees of OncoTherapy Science Inc. J.-H.P. is a scientific adviser of OncoTherapy Science Inc. Y.N. is a stockholder and an adviser of OncoTherapy Science Inc. A patent application (WO/2011/123419) has been filed for compounds OTS514 and OTS964. Data and materials availability: OTS514 and OTS964 can be obtained through material transfer agreement from OncoTherapy Science Inc.
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