Troublemaking HER3 Enzyme Trashed | October 27, 2014 Issue - Vol. 92 Issue 43 | Chemical & Engineering News
Volume 92 Issue 43 | p. 8 | News of The Week
Issue Date: October 27, 2014 | Web Date: October 23, 2014

Troublemaking HER3 Enzyme Trashed

Drug Discovery: Cancer-causing pseudokinase directed to cellular garbage can
Department: Science & Technology
News Channels: Biological SCENE
Keywords: HER3, proteasome, cancer, inhibitor
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A covalent inhibitor tags the cancer-related pseudokinase HER3 with the hydrophobic group adamantane, causing HER3 to interact with a chaperone. The chaperone delivers HER3 to the cellular garbage can, the proteasome, for disposal, impeding cancer-inducing HER3 dimerization.
Credit: Nat. Chem. Biol.
A schematic showing the disposal of HER3 protein.
 
A covalent inhibitor tags the cancer-related pseudokinase HER3 with the hydrophobic group adamantane, causing HER3 to interact with a chaperone. The chaperone delivers HER3 to the cellular garbage can, the proteasome, for disposal, impeding cancer-inducing HER3 dimerization.
Credit: Nat. Chem. Biol.

A new study shows how pseudokinases, signaling enzymes that cause cancers and blood diseases, can be inhibited effectively by small molecules, a feat many researchers in the field believed wasn’t possible. The work could lead to pseudokinase-targeted drugs that fight cancer and other conditions.

Forty-eight pseudokinases account for 9% of the 520 kinases found in humans, notes Nathanael S. Gray of Dana-Farber Cancer Institute, in Boston, who carried out the study with Dana-Farber colleague Pasi A Jänne, Craig M. Crews of Yale University, and coworkers (Nat. Chem. Biol. 2014, DOI: 10.1038/nchembio.1658).

The team focused on the pseudokinase HER3, a target for ovarian, breast, and lung cancer. Pseudokinases are so called because they have kinase active sites but lack key residues needed for normal kinase activity. HER3’s principal activity is not phosphate transfer but rather forming cancer-inducing dimers with other proteins.

Drug developers typically inhibit kinases by blocking adenosine triphosphate binding. But that strategy typically doesn’t work for pseudokinases.

Now, the Dana-Farber/Yale group has identified a compound called TX2-121-1 that attaches covalently to HER3’s kinase active site. An adamantane hydrophobic group riding along with the inhibitor causes HER3 to interact with a chaperone that delivers HER3 to the proteasome, the cellular trash can.

This blocks cancer-inducing HER3 dimerization in cells at the 1-μM level. “We are currently trying to get potency into the 100-nM range and exploring pharmacological properties, both needed before we move into any animal testing,” Gray says.

Pseudokinase specialist Natalia Jura of the University of California, San Francisco, comments that the HER3-elimination strategy is “a very promising beginning” and could be extended to blocking not only other pseudokinases but also conventional kinases that promote diseases by noncatalytic mechanisms.

 
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