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Molecular Cell Publishes Data on A Novel Form of Enzyme Inhibition of A Protein Homeostasis Target

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The Takeda Oncology Company has announced publication of an article in the journal Molecular Cell describing the mechanism of enzyme inhibition of MLN4924 a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of a protein homeostasis pathway.

MLN4924 is the first small molecule inhibitor that specifically targets this class of enzyme to be studied clinically, and is currently being studied in Phase I clinical trials.

NAE is an enzyme that modulates the level of proteins critical for the regulation of cancer cell growth and survival pathways. Preclinical data published in the journal Nature in April 2009 show that MLN4924 inhibition of NAE function alters these important cancer pathways and results in cancer cell death.

Preclinical data published as the cover story in Molecular Cell reveal that NAE uses MLN4924 to create its own inhibitor. NAE does this by forming an adduct, or new molecule, by combining MLN4924 and an NAE substrate called NEDD8. This adduct blocks the enzyme activity and thereby inhibits the NEDD8 pathway.

For the first time we have a compound that selectively inhibits the activation of the NEDD8 pathway, said James Brownell, Ph.D., Scientific Fellow, Millennium. Our research also found that compounds similar to MLN4924 form analogous adducts that inhibit activating enzymes related to NAE.

These findings illustrate an unprecedented mechanism for enzyme inhibition and suggest a general strategy for selective inhibition of NEDD8 and related pathways using small molecules.