title: Pharmacological targeting of the pseudokinase Her3.
abstract: Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Dodge
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.affiliation: 1] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
authors.forename: Durga
authors.initials: D
authors.lastname: Udayakumar
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Gurbani
authors.affiliation: Department of Molecular, Cellular and Development Biology, Yale University, New Haven, Connecticut, USA.
authors.forename: Hyun Seop
authors.initials: HS
authors.lastname: Tae
authors.affiliation: Primary and Stem Cell Systems, Life Technologies Corporation, Madison, Wisconsin, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Riddle
authors.affiliation: 1] Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Korea. [2] KU-KIST Graduate School of Converging Science and Technology, Seoul, Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: 1] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Molecular, Cellular and Development Biology, Yale University, New Haven, Connecticut, USA.
authors.forename: Craig M
authors.identifier: 0000000284562005
authors.initials: CM
authors.lastname: Crews
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nathanael S
authors.identifier: 0000000153547403
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000494:pharmacology*; D000218:Adamantane / Q000737:chemistry; D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D055503:Protein Multimerization; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000178:Acrylamides; D000218:Adamantane; D000225:Adenine; D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D003545:Cysteine; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C000594651:TX1-85-1; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human