title: Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein.
abstract: 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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Qingkai
authors.initials: Q
authors.lastname: Yang
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Bingwen
authors.initials: B
authors.lastname: Lu
authors.forename: Michael
authors.initials: M
authors.lastname: Cameron
authors.forename: Colleen
authors.initials: C
authors.lastname: Fearns
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Patricelli
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D048054:Mitogen-Activated Protein Kinase 7