Pharmacological targeting of the pseudokinase Her3

Title
Pharmacological targeting of the pseudokinase Her3
Authors
Ting XieSang Min LimKenneth D. WestoverMichael E. DodgeDalia ErcanScott B. FicarroDurga UdayakumarDeepak GurbaniHyun Seop TaeSteven M. Riddle심태보Jarrod A. MartoPasi A. JanneCraig M. CrewsNathanael S. Gray
Keywords
HER3
Issue Date
2014-12
Publisher
Nature chemical biology
Citation
VOL 10, 1006-1012
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.
URI
http://pubs.kist.re.kr/handle/201004/50839
ISSN
15524469
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KIST Publication > Article
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