2. Academic Validation
  3. Development of small molecules targeting the pseudokinase Her3

Development of small molecules targeting the pseudokinase Her3

  • Bioorg Med Chem Lett. 2015 Aug 15;25(16):3382-9. doi: 10.1016/j.bmcl.2015.04.103.
Sang Min Lim 1,  Ting Xie 1,  Kenneth D Westover 2,  Scott B Ficarro 3,  Hyun Seop Tae 4,  Deepak Gurbani 2,  Taebo Sim 5,  Jarrod A Marto 3,  Pasi A Jänne 6,  Craig M Crews 4,  Nathanael S Gray 7
Affiliations

Affiliations

  • 1 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.
  • 2 Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
  • 3 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.
  • 4 Departments of Chemistry, Pharmacology, and Molecular, Cellular and Development Biology, Yale University, New Haven, CT 06511, USA.
  • 5 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.
  • 6 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 7 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.
PMID: 26094118 DOI: 10.1016/j.bmcl.2015.04.103
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.

Keywords

Cancer; Her3; Hydrophobic tagging; Pseudokinase; Pyrazolopyrimidine.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-118998
    Her3 (ErbB3) Inhibitor