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Nat Chem Biol. 2014 Dec;10(12):1006-12. doi: 10.1038/nchembio.1658. Epub 2014 Oct 19.

Pharmacological targeting of the pseudokinase Her3.

Author information

1
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.
2
Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
3
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
4
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.
5
Department of Molecular, Cellular and Development Biology, Yale University, New Haven, Connecticut, USA.
6
Primary and Stem Cell Systems, Life Technologies Corporation, Madison, Wisconsin, USA.
7
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.
8
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.

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.

PMID:
25326665
PMCID:
PMC4232461
DOI:
10.1038/nchembio.1658
[Indexed for MEDLINE]
Free PMC Article
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