Only in Titles

           Search results for: MLN-4924 Mechanisms: NAE inhibitor   

paperclip

#26851293   2016/05/06 Save this To Up

The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR.

Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-κB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencing-defined poor-prognostic cancer hotspot mutations, and CD34(+)/CD38(-)/CD123(+) populations, but not normal CD34(+) progenitors. Finally, combined treatment markedly reduced tumor burden and significantly prolonged animal survival (P < .0001) in AML xenograft models with negligible toxicity, accompanied by pharmacodynamic effects observed in vitro. Collectively, these findings argue that MLN4924 and belinostat interact synergistically by reciprocally disabling the DDR in AML/MDS cells. This strategy warrants further consideration in AML/MDS, particularly in disease with unfavorable genetic aberrations.

1818 related Products with: The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR.

FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu BACTERIOLOGY BACTEROIDES TCP-1 theta antibody Sour Recombinant Thermostable Recombinant Thermostable Recombinant Thermostable Recombinant Human PKC the Recombinant Human PKC the Recombinant Human PKC the

Related Pathways

paperclip

#26676780   2016/02/12 Save this To Up

Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1.

HIV-1 Vpu decreases the exposure of epitopes within the viral envelope glycoprotein (Env) on the surface of infected cells by downregulating both BST2 and CD4. To test the hypothesis that inhibiting Vpu activity would increase the exposure of these epitopes and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC), we treated cells with the Nedd8 activation enzyme (NAE) inhibitor MLN4924, which inhibits the cullin1-based ubiquitin ligase complex coopted by Vpu to degrade cellular targets. Treatment of HeLa cells with MLN4924 or expression of a dominant negative mutant of cullin1 inhibited the Vpu-mediated downregulation of CD4 but not the downregulation of BST2. NAE inhibition also increased the surface exposure of CD4-induced epitopes within Env on HEK293 cells containing an inducible HIV genome, on infected CEM T cells, and on infected primary T cells. In contrast, the Vpu-mediated downregulation of BST2 was substantially inhibited by MLN4924 only when T cells were treated with alpha interferon (IFN-α) to induce high levels of BST2 expression. As reported previously, the absence of vpu or nef and even more so the combined absence of these two genes sensitized infected cells to ADCC. However, NAE inhibition affected ADCC minimally. Paradoxically, even in infected, IFN-treated cells in which NAE inhibition substantially rescued the surface level of BST2, the surface level of Env detected with an antibody recognizing a CD4-independent epitope (2G12) was minimally increased. Mutation of the C-terminal Vpu residue W76, which supports the ability of Vpu to stimulate virion release by displacing BST2 from assembly sites on the plasma membrane by a cullin1-independent mechanism, increased the exposure of Env detected by 2G12 on infected T cells. Thus, inhibiting the displacement function of Vpu together with its ability to degrade CD4 and BST2 may be required to sensitize infected cells to ADCC.

2290 related Products with: Pharmacologic Inhibition of Nedd8 Activation Enzyme Exposes CD4-Induced Epitopes within Env on Cells Expressing HIV-1.

HIV type O envelope antig HIV 2 gp36 envelope antig Recombinant HIV Type-O En Recombinant HIV Type-O En Recombinant HIV Type-O En Recombinant HIV-1 Envelop Recombinant HIV-1 Envelop Recombinant HIV-1 Envelop Recombinant HIV-1 Envelop Recombinant HIV-1 Envelop Recombinant HIV-1 Envelop Recombinant HIV-1 Envelop

Related Pathways

paperclip

#25899169   2016/01/04 Save this To Up

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications.

New therapeutic intervention strategies for the treatment of human malignancies are always desired. Approval of bortezomib as a front-line treatment for multiple myeloma highlighted the significance of ubiquitin-proteasome system (UPS) as a promising therapeutic target. However, due to the broad impact of proteasome inhibition, deleterious side effects have been reported with bortezomib treatment. Cullin RING ligases (CRLs)-mediated ubiquitin conjugation process is responsible for the ubiquitin conjugation of 20 % cellular proteins that are designated for degradation through the UPS, most of them are critical proteins involved in cell cycle progression, signaling transduction and apoptosis. Studies have depicted the upstream NEDDylation pathway that controls the CRL activity by regulating the conjugation of an ubiquitin-like-protein NEDD8 to the cullin protein in the complex. A specific pharmaceutical inhibitor of NEDD8 activating enzyme (NAE; E1) MLN4924 was recently developed and has been promoted to Phase I clinical trials for the treatment of several human malignancies. This article summarizes the most recent understanding about the process of NEDD8 conjugation, its relevance for cancer therapy and molecular mechanisms responsible for the potent anti-tumor activity of MLN4924.

1491 related Products with: Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications.

Multiple organ cancer tis Cellufine Formyl , 50 ml Cellufine Formyl Media Cellufine Formyl , 500 ml Cellufine Formyl Media Cellufine Formyl Media CA125, Ovarian Cancer An CA125, Ovarian Cancer An CA125, Ovarian Cancer An Formalin Solution (20%) Formalin Solution (20%) Formalin Solution (20%)

Related Pathways

paperclip

#25363690   2015/02/16 Save this To Up

MLN4924 sensitizes monocytes and maturing dendritic cells for TNF-dependent and -independent necroptosis.

MLN4924 prevents the formation of active cullin-RING ubiquitin ligase complexes and thus inhibits NF-κB signalling. Here, we evaluated the effects of this compound on monocytes and dendritic cells (DCs).

2028 related Products with: MLN4924 sensitizes monocytes and maturing dendritic cells for TNF-dependent and -independent necroptosis.

Androgen Receptor (Phosph Androgen Receptor (Phosph Rabbit Anti-Human Androge Rabbit Anti-Human Androge Androgen Receptor (Ab 650 anti CD16 NK cells, monoc AZD-3514 Mechanisms: Andr 17β-Acetoxy-2α-bromo-5 (5α,16β)-N-Acetyl-16-[2 (5α,16β)-N-Acetyl-16-ac 5α-N-Acetyl-2'H-androst- 5α-N-Acetyl-2'H-androst-

Related Pathways

paperclip

#24691136   2014/04/02 Save this To Up

Mutations in UBA3 confer resistance to the NEDD8-activating enzyme inhibitor MLN4924 in human leukemic cells.

The NEDD8-activating enzyme (NAE) initiates neddylation, the cascade of post-translational NEDD8 conjugation onto target proteins. MLN4924, a selective NAE inhibitor, has displayed preclinical anti-tumor activity in vitro and in vivo, and promising clinical activity has been reported in patients with refractory hematologic malignancies. Here, we sought to understand the mechanisms of resistance to MLN4924. K562 and U937 leukemia cells were exposed over a 6 month period to MLN4924 and populations of resistant cells (R-K562(MLN), R-U937(MLN)) were selected. R-K562(MLN) and R-U937(MLN) cells contain I310N and Y352H mutations in the NAE catalytic subunit UBA3, respectively. Biochemical analyses indicate that these mutations increase the enzyme's affinity for ATP while decreasing its affinity for NEDD8. These mutations effectively contribute to decreased MLN4924 potency in vitro while providing for sufficient NAE function for leukemia cell survival. Finally, R-K562(MLN) cells showed cross-resistance to other NAE-selective inhibitors, but remained sensitive to a pan-E1 (activating enzyme) inhibitor. Thus, our work provides insight into mechanisms of MLN4924 resistance to facilitate the development of more effective second-generation NAE inhibitors.

2995 related Products with: Mutations in UBA3 confer resistance to the NEDD8-activating enzyme inhibitor MLN4924 in human leukemic cells.

Human Migration Inhibitor Macrophage Colony Stimula Macrophage Colony Stimula Protease Inhibitor 15 ant Proteasome inhibitor PI31 Recombinant Human Interfe Human Urinary Trypsin Inh Human Urinary Trypsin Inh Human Urinary Trypsin Inh Recombinant Human WNT Inh Recombinant Human WNT Inh Recombinant Human WNT Inh

Related Pathways

  •  
  • No related Items
paperclip

#23527154   2013/03/25 Save this To Up

The IKK inhibitor Bay 11-7082 induces cell death independent from inhibition of activation of NFκB transcription factors.

Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells.

1277 related Products with: The IKK inhibitor Bay 11-7082 induces cell death independent from inhibition of activation of NFκB transcription factors.

Transcription factors: O Stat3 Peptide Inhibitor, Stat3 Peptide Inhibitor, IKK-ε Kinase Inhibitor I IKK-ε Kinase Inhibitor I Stat3 Activation Inhibito RDEA-119 (BAY-869766) Mec Rabbit Anti-Cell death in Rabbit Anti-Cell death in Rabbit Anti-Cell death in Rabbit Anti-Cell death in Rabbit Anti-Cell death in

Related Pathways

paperclip

#23100467   2013/01/04 Save this To Up

Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924.

MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents the ubiquitination and proteasomal degradation of substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but the genetic determinants conferring sensitivity to NAE inhibition are unknown. To address this gap in knowledge, we conducted a genome-wide siRNA screen to identify genes and pathways that affect the lethality of MLN4924 in melanoma cells. Of the 154 genes identified, approximately one-half interfered with components of the cell cycle, apoptotic machinery, ubiquitin system, and DNA damage response pathways. In particular, genes involved in DNA replication, p53, BRCA1/BRCA2, transcription-coupled repair, and base excision repair seemed to be important for MLN4924 lethality. In contrast, genes within the G(2)-M checkpoint affected sensitivity to MLN4924 in colon cancer cells. Cell-cycle analysis in melanoma cells by flow cytometry following RNAi-mediated silencing showed that MLN4924 prevented the transition of cells from S-G(2) phase after induction of rereplication stress. Our analysis suggested an important role for the p21-dependent intra-S-phase checkpoint and extensive rereplication, whereas the ATR-dependent intra-S-phase checkpoint seemed to play a less dominant role. Unexpectedly, induction of the p21-dependent intra-S-phase checkpoint seemed to be independent of both Cdt1 stabilization and ATR signaling. Collectively, these data enhance our understanding of the mechanisms by which inhibition of NEDD8-dependent ubiquitination causes cell death, informing clinical development of MLN4924.

2866 related Products with: Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924.

OxiSelect™ Cellular UV- Pfu DNA Polymerase protei Jurkat Cell Extract (Indu Jurkat Cell Extract (Indu Jurkat Cell Extract (Indu Jurkat Cell Extract (Indu Stat3 Peptide Inhibitor, Stat3 Peptide Inhibitor, Single Strand DNA Ligase, Single Strand DNA Ligase, Thermostable TDG Enzyme & BYL-719 Mechanisms: PI3K-

Related Pathways

paperclip

#22799561   2012/09/20 Save this To Up

MLN4924: a novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy.

The small ubiquitin-like molecule NEDD8 has been identified as an essential regulator of the activity of the cullin-RING E3 ubiquitin ligases (CRLs), which control the turnover of multiple proteins with fundamental roles in cancer biology. The aberrant function of the NEDD8 cascade within the context of malignancy makes it an attractive target for the development of novel anticancer agents. MLN4924 is a first-in-class inhibitor of the proximal regulator of the NEDD8 system (NEDD8-activating enzyme, NAE) that has entered Phase-I trials for cancer therapy and has established that significant therapeutic benefit can be achieved by antagonizing NEDD8-mediated protein degradation.

2232 related Products with: MLN4924: a novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy.

Goat Anti- UBE2F NEDD8-co CA125, Ovarian Cancer An CA125, Ovarian Cancer An CA125, Ovarian Cancer An MOUSE ANTI BOVINE ROTAVIR Bone Morphogenetic Protei Growth Differentiation Fa Amplite™ Fluorimetric F Caspase-3 Inhibitor Z-DEV Caspase-3 Inhibitor Z-DEV Caspase-Family Inhibitor Caspase-Family Inhibitor

Related Pathways