Cancer Cell - Pharmacological Inhibition of BMK1 Suppresses Tumor Growth through Promyelocytic Leukemia Protein

Pharmacological Inhibition of BMK1 Suppresses Tumor Growth through Promyelocytic Leukemia Protein

Cancer Cell, Volume 18, Issue 3, 258-267, 14 September 2010
Copyright © 2010 Elsevier Inc. All rights reserved.
10.1016/j.ccr.2010.08.008

Authors
Qingkai Yang, Xianming Deng, Bingwen Lu, Michael Cameron, Colleen Fearns, Matthew P. Patricelli, John R. Yates, Nathanael S. Gray, Jiing-Dwan LeeSee

AffiliationsHint: Rollover Authors and Affiliations Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA ActivX Biosciences, 11025 North Torrey Pines Road, La Jolla, CA 92037, USA Dana Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA Translational Research Institute-Drug Metabolism and Pharmacokinetics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA Corresponding author These authors contributed equally to this work

Highlights
•Development of a potent inhibitor, XMD8-92, for BMK1 kinase
•XMD8-92 significantly inhibits tumor growth in animal
•BMK1 inhibits p21 expression through PML

Summary
BMK1 is activated by mitogens and oncogenic signals and, thus, is strongly implicated in tumorigenesis. We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation. Furthermore, activated BMK1 notably inhibited PML-dependent activation of p21. To further investigate the BMK-mediated inhibition of the tumor suppressor activity of PML in tumor cells, we developed a small-molecule inhibitor of the kinase activity of BMK1, XMD8-92. Inhibition of BMK1 by XMD8-92 blocked tumor cell proliferation in vitro and significantly inhibited tumor growth in vivo by 95%, demonstrating the efficacy and tolerability of BMK1-targeted cancer treatment in animals.

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Cancer Cell - Pharmacological Inhibition of BMK1 Suppresses Tumor Growth through Promyelocytic Leukemia Protein