title: Development of small molecules targeting the pseudokinase Her3.
abstract: Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.affiliation: Departments of Chemistry, Pharmacology, and Molecular, Cellular and Development Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Hyun Seop
authors.initials: HS
authors.lastname: Tae
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Gurbani
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Seongbuk-gu, Seoul 136-713, Republic of Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Departments of Chemistry, Pharmacology, and Molecular, Cellular and Development Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: Nathanael_Gray@dfci.harvard.edu.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000178:Acrylamides; C000607557:N-(2-(4-(3-(3-acrylamido-4-phenoxyphenyl)-4-amino-1H-pyrazolo(3,4-d)pyrimidin-1-yl)piperidin-1-yl)ethyl)-4-(1-adamantanyl)-2-methylbutanamide; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; C000594651:TX1-85-1; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D000225:Adenine
keywords: Cancer; Her3; Hydrophobic tagging; Pseudokinase; Pyrazolopyrimidine