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Formula | C21H25N5O4S |
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Molecular Weight | 443.52 | CAS No. | 905579-51-3 | ||||
Solubility (25°C)* | In vitro | DMSO | 89 mg/mL (200.66 mM) | ||||
Ethanol | 45 mg/mL (101.46 mM) | ||||||
Water | Insoluble | ||||||
In vivo (Add solvents to the product individually and in order) |
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* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.) |
Description | MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM. | ||
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Targets |
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In vitro | MLN4924 is structurally related to adenosine 59-monophosphate (AMP)—a tight binding product of the NAE reaction. MLN4924 (3 μM) selectively inhibits NAE in HCT-116 cell lysates. MLN4924 (3 μM) inhibits overall protein turnover by <9% in HCT-116 cells. MLN4924 results in a dose-dependent decrease of Ubc12–NEDD8 thioester and NEDD8–cullin conjugates with an IC50 < 0.1 μM in HCT-116 cells, resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2, but not non-CRL substrates. MLN4924 (3 μM) leads cells to accumulate in S-phase as early as 8 hours and results in a significant fraction of cells contained 4N DNA content by 24 hours in HCT-116 cells. [1] MLN4924 (3 μM) results in rapid accumulation of pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappaB pathway inhibition in ABC DLBCL cells. [2] MLN4924 (1 μM) triggers DNA replication and inhibit cell proliferation by stabilizing the DNA replication factor Cdt1, a substrate of cullins 1 and 4. MLN4924 (1 μM) , which is sufficient to elevate Cdt1 for 4-5 hours, is found to be sufficient to induce DNA replication and to activate apoptosis and senescence pathways. [3] MLN4924 treatment induces the characteristics of senescence phenotypes as evidenced by enlarged and flattened cellular morphology and positive staining of senescence-associated β-Gal. MLN4924-induced senescence is associated with cellular response to DNA damage, triggered by accumulation of DNA-licensing proteins CDT1 and ORC1, as a result of inactivation of CRL/SCF E3s. MLN4924-induced senescence is irreversible and coupled with persistent accumulation of p21 and sustained activation of DNA damage response. [4] | ||
In vivo | MLN4924 (60 mg/kg) results in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration in HCT-116 tumour-bearing mice, with maximal effect 1–2 hours post-dose. MLN4924 (60 mg/kg) also leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumour-bearing mice. MLN4924 (60 mg/kg) leads to DNA damage in the tumour indicated by the increased levels of phosphorylated CHK1 in HCT-116 tumour-bearing mice. MLN4924 administered on a BID schedule at 30 mg/kg and 60 mg/kg inhibits tumour growth with T/C values of 0.36 and 0.15, respectively, in mice bearing HCT-116 xenografts. [1] MLN4924 (60 mg/kg) blocks NAE pathway biomarkers and results in complete tumor growth inhibition in mice bearing human xenograft tumors of ABC- and GCB-DLBCL. MLN4924 (60 mg/kg) results in NF-kappaB pathway inhibition accompanied by tumor regressions in primary human tumor mice models of ABC-DLBCL. [2] | ||
Features | A mechanism-based inhibitor of NAE, and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. |
Kinase Assay:[1] |
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Cell Assay:[1] |
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Animal Study:[1] |
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Data from [Data independently produced by , , Leukemia, 2019, 33(1):171-180]
Data from [Data independently produced by , , J Exp Clin Cancer Res, 2018, 37(1):165]
Data from [Data independently produced by , , J Immunol, 2016, 196(7):3117-23]
Tet methylcytosine dioxygenase 2 (TET2) deficiency elicits EGFR-TKI (tyrosine kinase inhibitors) resistance in non-small cell lung cancer [ Signal Transduct Target Ther, 2024, 9(1):65] | PubMed: 38461173 |
Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors [ Mol Cancer, 2024, 23(1):242] | PubMed: 39478560 |
Noncanonical assembly, neddylation and chimeric cullin-RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex [ Nat Struct Mol Biol, 2024, 10.1038/s41594-024-01257-y] | PubMed: 38605244 |
Small molecule induced STING degradation facilitated by the HECT ligase HERC4 [ Nat Commun, 2024, 15(1):4584] | PubMed: 38811577 |
A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins [ Nat Commun, 2024, 15(1):2485] | PubMed: 38509117 |
Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response [ EMBO J, 2024, 43(6):904-930] | PubMed: 38337057 |
Retinoic acid-induced protein 14 links mechanical forces to Hippo signaling [ EMBO Rep, 2024, 25(9):4033-4061] | PubMed: 39160347 |
Cereblon mediates macrophage differentiation and microglial phagocytosis by regulating calpain protease activity [ Biomed Pharmacother, 2024, 180:117606] | PubMed: 39454366 |
AAMP and MTSS1 Are Novel Negative Regulators of Endothelial Barrier Function Identified in a Proteomics Screen [ Cells, 2024, 13(19)1609] | PubMed: 39404373 |
Inducing Receptor Degradation as a Novel Approach to Target CC Chemokine Receptor 2 (CCR2) [ Int J Mol Sci, 2024, 25(16)8984] | PubMed: 39201670 |
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