title: UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer.
abstract: OBJECTIVE
  c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.
  
  
  METHODS
  We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts.
  
  
  RESULTS
  We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.
  
  
  CONCLUSIONS
  In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 22(20); 5087-96. ©2016 AACR.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Rabia A
authors.initials: RA
authors.lastname: Gilani
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Sameer
authors.initials: S
authors.lastname: Phadke
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Li Wei
authors.initials: LW
authors.lastname: Bao
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lachacz
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Michele L
authors.initials: ML
authors.lastname: Dziubinski
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kristoffer R
authors.initials: KR
authors.lastname: Brandvold
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Steffey
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Kwarcinski
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Graveel
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Kidwell
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. soellner@med.umich.edu smerajve@med.umich.edu.
authors.forename: Sofia D
authors.initials: SD
authors.lastname: Merajver
authors.affiliation: Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan. soellner@med.umich.edu smerajve@med.umich.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Soellner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000502:physiology; D000081247:CSK Tyrosine-Protein Kinase; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D000069439:Dasatinib