Merck

Pharmacological targeting of the pseudokinase Her3.

Nature chemical biology (2014-10-20)
Ting Xie, Sang Min Lim, Kenneth D Westover, Michael E Dodge, Dalia Ercan, Scott B Ficarro, Durga Udayakumar, Deepak Gurbani, Hyun Seop Tae, Steven M Riddle, Taebo Sim, Jarrod A Marto, Pasi A Jänne, Craig M Crews, Nathanael S Gray
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
L-Cysteine, produced by Wacker Chemie AG, Burghausen, Germany, ≥98.0%
Supelco
L-Cysteine, certified reference material, TraceCERT®
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L-Cysteine, from non-animal source, BioReagent, suitable for cell culture, ≥98%
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L-Cysteine, BioUltra, ≥98.5% (RT)
SAFC
L-Cysteine
Sigma-Aldrich
Adamantane, ≥99%
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Adenine, ≥99%
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Adenine, BioReagent, suitable for plant cell culture, ≥99%
Sigma-Aldrich
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Supelco
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