生物活性

• 描述NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways^[3]. MLN4924 is a potent and selective inhibitor of NAE with an IC₅₀ value of 0.004 μM^[3]. MLN4924 inhibits overall protein turnover in cultured HCT-116 cells. Treatment of HCT-116 cells with MLN4924 for 24 h results in a dose-dependent decrease of Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, with an IC₅₀ < 0.1 μM, resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2 (also known as NFE2L2), but not non-CRL substrates^[3]. MLN4924 rapidly inhibits cullin 1 neddylation and remarkably suppresses growth and survival as well as migration in a dose-and time-dependent manner in gastric cancer cells, and significantly suppresses migration by transcriptionally activating E-cadherin and repressing MMP-9^[4]. MLN492410, 30 or 60 mg/kg, s.c. leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumor-bearing mice, and decreases NEDD8-cullin levels in normal mouse tissue as illustrated in mouse bone marrow cells. MLN4924 administered on a BID schedule at 30 and 60 mg/kg inhibits tumor growth with T/C values of 0.36 and 0.15, respectively^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  K562 cells	-	Proliferation assay	72 h	Antiproliferative activity against human K562 cells after 72 hrs by CellTiter-Glo assay, EC50=0.108 μM	24900352

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03013998	Previously Untreated Acute Mye... more >>loid Leukemia Collapse <<	Phase 1 Phase 2	Recruiting	December 2021	United States, Arizona ... more >> Mayo Clinic Arizona Recruiting Phoenix, Arizona, United States, 85054 Principal Investigator: Lisa Sproat, MD          United States, California UCLA Ronald Reagan Medical Center Recruiting Los Angeles, California, United States, 90095 Principal Investigator: Gary Schiller, MD          University of California, San Francisco Recruiting San Francisco, California, United States, 94143 Principal Investigator: Gabriel Mannis, MD          United States, Colorado University of Colorado Recruiting Denver, Colorado, United States, 80203 Principal Investigator: Dan Pollyea, MD          United States, Florida Mayo Clinic Florida Recruiting Jacksonville, Florida, United States, 32224 Principal Investigator: James Foran, MD          United States, Georgia Emory University Recruiting Atlanta, Georgia, United States, 30308 Principal Investigator: William Blum, MD          United States, Illinois University of Chicago Recruiting Chicago, Illinois, United States, 60637 Principal Investigator: Wendy Stock, MD          United States, Maryland University of Maryland Medical Center Recruiting Baltimore, Maryland, United States, 21201 Principal Investigator: Maria Baer, MD          United States, New York Memorial Sloan Kettering Cancer Center Recruiting New York, New York, United States, 10065 Principal Investigator: Eytan M Stein, MD          United States, Ohio Ohio State University Recruiting Columbus, Ohio, United States, 43210 Principal Investigator: John C Byrd, MD          Principal Investigator: Alice Mims, MD          Principal Investigator: Alison R Walker, MD, MPH          United States, Oregon Oregon Health & Science University Recruiting Portland, Oregon, United States, 97239 Principal Investigator: Uma Borate, MD          United States, Texas University of Texas Southwestern Recruiting Dallas, Texas, United States, 75390 Principal Investigator: Prapti Patel, MD          United States, Utah Huntsman Cancer Institute, University of Utah Recruiting Salt Lake City, Utah, United States, 84112 Principal Investigator: Michael Deininger, MD, PhD Collapse <<
  NCT03228186	Non-small Cell Lung Cancer	Phase 2	Recruiting	September 1, 2020	United States, Michigan ... more >> University of Michigan Comprehensive Cancer Center Recruiting Ann Arbor, Michigan, United States, 48187 Contact: Gregory Kalemkerian, M.D.    734-647-8921    kalemker@umich.edu    Principal Investigator: Gregory Kalemkerian, M.D. Collapse <<
  NCT03238248	Myelodysplastic Syndromes ... more >> Myeloproliferative Neoplasm Collapse <<	Phase 2	Recruiting	July 2023	United States, Florida ... more >> University of Miami Miller School of Medicine Recruiting Miami, Florida, United States, 33136 Principal Investigator: Justin Watts, MD          United States, Kansas University of Kansas Cancer Center Recruiting Westwood, Kansas, United States, 66205 Principal Investigator: Barry Skikne, MD          United States, New York Memorial Sloan-Kettering Not yet recruiting New York, New York, United States, 10065 Principal Investigator: Virginia Klimek, MD          University of Rochester Medical Center Not yet recruiting Rochester, New York, United States, 14642 Principal Investigator: Jason Mendler, MD          United States, Tennessee Vanderbilt-Ingram Cancer Center Recruiting Nashville, Tennessee, United States, 37232 Contact: Vanderbilt-Ingram Service for Timely Access          Contact    800-811-8480 Collapse <<

• 更多
• 参考文献

• [1] Chang PJ, Chen LW, et al. Effects of the NEDD8-Activating Enzyme Inhibitor MLN4924 on Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus. J Virol. 2017 Sep 12;91(19). pii: e00505-17.

  [2] Tong S, Si Y, et al. MLN4924 (Pevonedistat), a protein neddylation inhibitor, suppresses proliferation and migration of human clear cell renal cell carcinoma. Sci Rep. 2017 Jul 17;7(1):5599.

  [3] Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB, Langston SP. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6. doi: 10.1038/nature07884. PMID: 19360080.

  [4] Lan H, Tang Z, Jin H, Sun Y. Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells. Sci Rep. 2016 Apr 11;6:24218. doi: 10.1038/srep24218. PMID: 27063292; PMCID: PMC4827092.