1. Pharmacological targeting of the pseudokinase Her3
- Author
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Michael E. Dodge, Nathanael S. Gray, Hyun Seop Tae, Pasi A. Jänne, Jarrod A. Marto, Dalia Ercan, Taebo Sim, Deepak Gurbani, Kenneth D. Westover, Scott B. Ficarro, Craig M. Crews, Sang M in Lim, Ting Xie, Durga Udayakumar, and Steven M. Riddle
- Subjects
Receptor, ErbB-3 ,Receptor, ErbB-2 ,Proteolysis ,High-throughput screening ,Adamantane ,Antineoplastic Agents ,Biology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Adenosine Triphosphate ,0302 clinical medicine ,Catalytic Domain ,Cell Line, Tumor ,medicine ,Humans ,Cysteine ,Molecular Targeted Therapy ,skin and connective tissue diseases ,Protein Kinase Inhibitors ,Molecular Biology ,Cell Proliferation ,030304 developmental biology ,Acrylamides ,0303 health sciences ,medicine.diagnostic_test ,Cell growth ,Kinase ,Adenine ,Cell Biology ,Proto-Oncogene Proteins c-met ,Small molecule ,3. Good health ,Gene Expression Regulation, Neoplastic ,Molecular Docking Simulation ,body regions ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Protein Multimerization ,Signal transduction ,Hydrophobic and Hydrophilic Interactions ,Adenosine triphosphate ,Signal Transduction - 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.
- Published
- 2014
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