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news.Millennium: The Takeda Oncology Company has announced the publication of data 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. The article was published in the journal, Molecular Cell.
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The company claims that 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.
Reportedly, the preclinical data revealed 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 known as NEDD8. This adduct blocks the enzyme activity and thereby inhibits the NEDD8 pathway.
James Brownell, scientific fellow at Millennium, said: “For the first time we have a compound that selectively inhibits the activation of the NEDD8 pathway. 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.”
Joseph Bolen, chief scientific officer at Millennium, said:. “This publication of MLN4924 data is just one example of Millennium’s success in defining new cancer drug targets and potential therapeutics, including MLN4924, which is now being studied in Phase I clinical trials.”