Millennium publishes article on MLN4924 pathway mechanism in lymphoma

Millennium: The Takeda Oncology Company today announced the publication of an article in the journal Blood describing the novel mechanism of action of MLN4924 through targeted pathway modulation in diffuse large B-cell lymphoma (DLBCL). MLN4924 is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. It is the first small molecule inhibitor specifically targeting this class of enzyme to be studied clinically, and is currently being examined in Phase I clinical trials.

“The research highlighted in this paper shows a strong rationale for the clinical development of MLN4924 in lymphoma, particularly NF-κB dependent lymphomas, and in additional cancers with NF-κB implications”

NAE is an enzyme that modulates the level of proteins critical for the regulation of cancer cell growth and survival pathways. One such pathway that is controlled by NAE is the NF-κB signaling pathway, known to be important in the survival of some types of DLBCL. The publication in Blood demonstrates that MLN4924 has antitumor activity in preclinical DLBCL models through the inhibition of the NF-κB pathway. In addition, the publication showed that MLN4924 has antitumor activity in non-NF-κB dependent DLBCLs through other mechanisms including DNA re-replication.

"The research highlighted in this paper shows a strong rationale for the clinical development of MLN4924 in lymphoma, particularly NF-κB dependent lymphomas, and in additional cancers with NF-κB implications," said Peter G. Smith, Senior Scientist at Millennium and lead author of the publication.

"Our dedication to innovation in the laboratory has resulted in Millennium being a leading company in protein homeostasis. MLN4924 is one of three compounds we have advanced into the clinic as a result of this commitment to groundbreaking research," said Joseph Bolen, Ph.D., Chief Scientific Officer, Millennium.

Previously, preclinical data published in the journal Nature in April 2009 showed that MLN4924 inhibition of NAE function alters important cancer pathways and results in cancer cell death. Preclinical data published as the cover story in Molecular Cell in January 2010 revealed that NAE uses MLN4924 to create its own inhibitor by forming an adduct, or new molecule, by combining MLN4924 and an NAE substrate called NEDD8.

Source : Millennium