Pharmacological Targeting of the Pseudokinase Her3

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Pharmacological Targeting of the Pseudokinase Her3

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Title: Pharmacological Targeting of the Pseudokinase Her3
Author: Xie, Ting; Lim, Sang Min; Westover, Kenneth D.; Dodge, Michael E.; Ercan, Dalia; Ficarro, Scott B.; Udayakumar, Durga; Gurbani, Deepak; Tae, Hyun Seop; Riddle, Steven M.; Sim, Taebo; Marto, Jarrod A.; Jänne, Pasi A.; Crews, Craig M.; Gray, Nathanael S.

Note: Order does not necessarily reflect citation order of authors.

Citation: Xie, T., S. M. Lim, K. D. Westover, M. E. Dodge, D. Ercan, S. B. Ficarro, D. Udayakumar, et al. 2014. “Pharmacological Targeting of the Pseudokinase Her3.” Nature chemical biology 10 (12): 1006-1012. doi:10.1038/nchembio.1658. http://dx.doi.org/10.1038/nchembio.1658.
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Abstract: Her3 (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 significant kinase activity. Here we report 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 the approximately 60 other pseudokinases found in human cells.
Published Version: doi:10.1038/nchembio.1658
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232461/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295790
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