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MLN-4924

NAE inhibitor MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with potential antineoplastic activity. NAE inhibitor MLN4924 binds to and inhibits NAE, which may result in the inhibition of tumor cell proliferation and survival. NAE activates Nedd8 (Neural precursor cell expressed, developmentally down-regulated 8), an ubiquitin-like (UBL) protein that modifies cellular targets in a pathway that is parallel to but distinct from the ubiquitin-proteasome pathway (UPP). Functioning in diverse regulatory activities, proteins conjugated to UBLs like Nedd8 typically are not targeted for proteasomal degradation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

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: http://ash.confex.com/ash/2008/webprogram/Paper9916.html).

 Current developer:   Millennium Pharmaceuticals ( the Takeda Oncology Company)

1. Brownell, James E.; Sintchak, Michael D.; Gavin, James M.; Liao, Hua; Bruzzese, Frank J.; Bump, Nancy J.; Soucy, Teresa A.; Milhollen, Michael A.; Yang, Xiaofeng; Burkhardt, Anne L.; Ma, Jingya; Loke, Huay-Keng; Lingaraj, Trupti; Wu, Dongyun; Hamman, Kristin B.; Spelman, James J.; Cullis, Courtney A.; Langston, Steven P.; Vyskocil, Stepan; Sells, Todd B.; Mallender, William D.; Visiers, Irache; Li, Ping; Claiborne, Christopher F.; Rolfe, Mark; Bolen, Joseph B.; Dick, Lawrence R. Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Molecular Cell (2010), 37(1), 102-111. 

2. Soucy, Teresa A.; Smith, Peter G.; Milhollen, Michael A.; Berger, Allison J.; Gavin, James M.; Adhikari, Sharmila; Brownell, James E.; Burke, Kristine E.; Cardin, David P.; Critchley, Stephen; Cullis, Courtney A.; Doucette, Amanda; Garnsey, James J.; Gaulin, Jeffrey L.; Gershman, Rachel E.; Lublinsky, Anna R.; McDonald, Alice; Mizutani, Hirotake; Narayanan, Usha; Olhava, Edward J.; Peluso, Stephane; Rezaei, Mansoureh; Sintchak, Michael D.; Talreja, Tina; Thomas, Michael P.; Traore, Tary; Vyskocil, Stepan; Weatherhead, Gabriel S.; Yu, Jie; Zhang, Julie; Dick, Lawrence R.; Claiborne, Christopher F.; Rolfe, Mark; Bolen, Joseph B.; Langston, Steven P. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature (London, United Kingdom) (2009), 458(7239), 732-736.

3. Langston, Steven P.; Olhava, Edward J.; Vyskocil, Stepan. Preparation of purine nucleoside derivatives as antitumor agents and inhibitors of E1 activating enzymes. PCT Int. Appl. (2007), 174 pp. CODEN: PIXXD2 WO 2007092213

4. Critchley, Stephen; Gant, Thomas G.; Langston, Steven P.; Olhava, Edward J.; Peluso, Stephane. Preparation of nucleoside derivatives as inhibitors of E1 activating enzymes. PCT Int. Appl. (2006), 214pp. CODEN: PIXXD2 WO 2006084281