Journal
NATURE CHEMICAL BIOLOGY
Volume 10, Issue 12, Pages 1006-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1658
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Funding
- Dana Farber Cancer Institute Lander Fellowship
- Claudia Adams Barr Program Award
- US National Institutes of Health (NIH) [AI 084140-03]
- Cancer Prevention Research Institute of Texas [R1207]
- National Research Foundation of Korea [NRF-2011-0028676]
- NIH [P01 CA154303]
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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.
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