Xie, TingLim, Sang MinWestover, Kenneth D.Dodge, Michael E.Ercan, DaliaFicarro, ScottUdayakumar, DurgaGurbani, DeepakTae, Hyun SeopRiddle, Steven M.Sim, TaeboMarto, JarrodJänne, Pasi A.Crews, Craig M.Gray, Nathanael2015-07-132014Xie, 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.1658.1552-4450http://nrs.harvard.edu/urn-3:HUL.InstRepos:17295790Her3 (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.en-USJournal Article2015-07-1310.1038/nchembio.1658