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Bioorg Med Chem Lett. 2015 Aug 15;25(16):3382-9. doi: 10.1016/j.bmcl.2015.04.103. Epub 2015 May 11.

Development of small molecules targeting the pseudokinase Her3.

Author information

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.

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

PMID:
26094118
PMCID:
PMC4633287
DOI:
10.1016/j.bmcl.2015.04.103
[Indexed for MEDLINE]
Free PMC Article

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