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KI1011MLN492410 mg$512

Chemical Characteristic

Product NameMLN4924
CAS No.905579-51-3
Molecular Weight 443.52
FormulaC21H25N5O4S
Chemical NameSulfamic acid [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl ester
SmilesS(=O)(=O)(OCC1[C@H](C[C@@H](C1)n1c2ncnc(c2cc1)NC1CCc2ccccc12)O)N
Chemical Structure

Biological activities

MLN4924 is a selective NEDD8-activating enzyme inhibitor. The IC50 of MLN4924 is 5 nM against the NEDD8-activating enzyme. [1] MLN4924 significantly inhibits the growth of MiaPaCa-2 and BxPC-3 cells with IC50 of 45 and 177 nM, respectively, in an ATPlite-based 7-day cell proliferation assay. MLN4924 dose-dependently inhibits colony formation with an IC50 of minimal 25 nM, in a standard clonogenic survival assay with MLN4924 in the culture medium for 7 to 9 days. MLN4924 suppresses the growth of H1299 cancer cells and MRC5 normal cells with IC50 of 83 and 429 nM, respectively. MLN4924 inhibits the growth of clonogenic survival of H1299 cells and MRC5 normal cells with IC50 of 50 and 200 nM, respectively. Specifically, MLN4924 at doses of ranging from 20 to 100 nM effectively inhibits cullin neddylation. MLN4924 sensitizes pancreatic cancer cells to ionizing radiation in vitro.[2] In addition, MLN4924 inhibits the PPTP cell lines with an IC50 of 143 nM.[3] Moreover, MLN4924 at 2.5 µM induces autophagy in autophagy-competent Atg5+/+ MEFs. MLN4924 causes accumulation of DEPTOR and HIF1α. [4] In vivo, MLN4924 completely inhibits the growth of tumor growth in mice bearing human xenograft tumors of ABC- and GCB-DLBCL.[5]

Protocols

In vitro MLN4924 is dissolved in 0.1% dimethyl sulfoxide.[5]

References

[1] Brownell JE, et al. Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol Cell. 2010, 37(1): 102-111.
[2] Wei D, et al. Radiosensitization of human pancreatic cancer cells by MLN4924, an investigational NEDD8-activating enzyme inhibitor. Cancer Res. 2012, 72(1): 282-293.
[3] Smith MA, et al. Initial testing of the investigational NEDD8-activating enzyme inhibitor MLN4924 by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012, 59(2): 246-253.
[4] Zhao Y, et al. Targeting Cullin-RING ligases by MLN4924 induces autophagy via modulating the HIF1-REDD1-TSC1-mTORC1-DEPTOR axis. Cell Death Dis. 2012, 3: e386.
[5] Milhollen MA, et al. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood. 2010, 116(9): 1515-1523.

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