MLN-4924

MLN4924 is a first-in-class cancer drug that inhibits the Nedd8-activating enzyme (NAE).
In vivo administration of MLN4924 to mice bearing xenograft tumors of OCI-Ly10 and OCI-Ly19 resulted in a pharmacodynamic response of NAE pathway inhibition. In both models, a single dose of MLN4924 resulted in time and dose-dependent inhibition of total neddylated cullin levels and stabilization of CDL substrates including the CDL3Keap1 substrate, Nrf-2. Notably, in the OCI-Ly10 model, a single dose of MLN4924 resulted in a marked elevation of pIkBa levels, indicative of NF-kB pathway inhibition, and induction of apoptosis. In both OCI-Ly10 and OCI-Ly19 xenograft models, inhibition of the NAE pathway following repeated daily and intermittent dosing of MLN4924 translated into significant tumor growth inhibition. In the OCI-Ly10 model tumor regressions were observed showing this model to be particularly sensitive to MLN4924 treatment, reflecting the addiction of these tumors to NF-kB signaling. Additionally we demonstrate an inhibition of the NAE pathway and NF-KB signaling in a primary human tumor DLBCL xenograft model (PHTX-22L) resulting in tumor regressions following MLN4924 treatment. In summary, in tumors dependent on NF-kB signaling for growth and survival, MLN4924 inhibition of CDL activity provides a novel mechanism for targeted NF-kB pathway modulation and therapeutic intervention. In addition, these data demonstrate that MLN4924 is a novel agent that has broad activity in pre-clinical models of lymphoma. (source: Michael Milhollen, Usha Narayanan*, Allison J Berger, Michael Thomas, Tary Traore, Jie Yu, Julie Zhang, Erik Koenig, James J. Garnsey, Steven P. Langston, Teresa A Soucy, and Peter G Smith, MLN4924, a Novel Small Molecule Inhibitor of Nedd8-Activating Enzyme, Demonstrates Potent Anti-Tumor Activity in Diffuse Large B-Cell Lymphom, 50th ASH Annual Meeting and Exposition, or see website: