Pharmacological targeting of the pseudokinase Her3

Ting Xie, Sang M in Lim, Kenneth D. Westover, Michael E. Dodge, Dalia Ercan, Scott B. Ficarro, Durga Udayakumar, Deepak Gurbani, Hyun S eop Tae, Steven M. Riddle, Taebo Sim, Jarrod A. Marto, Pasi A. Jänne, Craig M. Crews, Nathanael S. Gray

Research output: Contribution to journalArticle

83 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1006-1012
Number of pages7
JournalNature chemical biology
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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