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MLN4924

It is a small novel synthetic molecule/ compound, highly selective in its action, and can be used to inhibit the NAE. NAE is defined as the NEDD8 activating enzyme. Different studies showed that this small NEDD8 molecule plays an important role in the regulation of the activity of CRLs. These CLRs (cullin-RING E3 ubiquitin ligases) are essential components of cancer biology as they control the turnover of different kinds of proteins. So, this NEED8 cascade can be targeted to control the malignancy of cancer for the development of anti-cancer drugs. For this purpose, researchers stated that the MLN 4924 (GC15086) can be the priority. It is because it inhibits the NAE and thus regulates the NEDD8 enzyme system. All these studies now entered into the phase 1 trials of antitumor therapy.

Structure of MLN 4924

Figure 1: Structure of MLN 4924

Researchers also confirmed that by antagonization of the NEDD8-mediated protein degradation, this anticancer therapy can be significantly affected. Previously published studies explained that the dysregulation in the degradation of the proteins plays a crucial role in the development of cancers etc. As we know that protein homeostasis helps the cells to perform important cellular events including the progression of the cell cycle, cell death events, and signal transduction. This protein homeostasis is regulated with the help of the main 2 intracellular systems. One is the UPS which is called a ubiquitin-proteasome system and the other one is the autophagy system. These 2 systems regulate the timed destruction of protein to maintain protein homeostasis. UPS mainly regulated the proteins which are short-lived through three different types of enzymes including E1, E2, and E3 called ubiquitin-activating, conjugating, and ligases enzymes. while the autophagy system regulates the bulk level of proteins. The complete NEDDylation pathway is described in figure 2.

NEDDylation system

Figure 2: NEDDylation system

In the tumor cells, this protein turnover is somewhat deregulated which leads to the progression of diseases, progression of cancer and imparts resistance against the different drugs. When MLN 4924 binds to the active site of the NAE, it results in the formation of the adduct which is stable and thus causes an interruption in the formation of the thioester of ubc12-NEDD8. Although this complex is similar to the NEDD8 adenylate, this inhibits the cascade because it can not be further processed. Studies showed that this novel compound is a selective inhibitor of NEDD8, but it also has a tad inhibitory activity against the other UBL E1s which include the SAE and UAE. Moreover, it also inhibits the formation of NEDD8-cullin conjugate and the NEDD8-ubc12. This leads to the disruption in the turnover of different CLR targets like NRF2, cyclin E, IkB, CDT1, and P27. Results stated that this action of MLN4924 is time and dose-dependent in the mice model or the cell lines which are under experiment. One of the in-vitro studies promising the antitumor effects of MLN4924 in different laboratory animal models. They stated that the MLN 4924 increase the apoptosis and the senescence of the cancer cells. Similarly, due to the inhibitory effect of NAE, this novel compound increases the accumulation of CDT1, which results in the re-replication of the DNA and an increase in the damage of DNA. It also inhibits the activity of NF-κB (https://www.glpbio.com/research-area/immunology/nf.html) through stabilizing of IB, and by the decrease in several targeted protein expressions (FLIP, SOD2, etc.). Researchers considered that this apoptotic effect of MLN4924 is due to the increase in oxidative stress in the cancer cells.

mechanism of action of MLN 4924

 Figure 3: mechanism of action of MLN 4924

 One of the studies conducted on the role of MLN 4924 in the ischemic brain injury in the mice model suggested that this novel compound by inhibiting the NEDD8 activating enzyme can reduce the level of ischemic brain injury in the mice. Although the role of the NAE pathway is somewhat elusive in ischemic brain injury but is observed and reported that the level of conjugation of NEDD8 is increased after the ischemic brain injury. During the experiment, researchers found that the treatment of the mice model with MLN 4924 during the experiment can improve the outcome of the stroke by inactivation the CRL. This also decreases brain infarction and increases the accumulation level of NF1 (Neurofibromatosis 1) thus leading to a reduced level of BBB breakdown. Researchers demonstrated that the after the ischemic stroke, the NEDDylation is upregulated in the brain cells and activated in the intraparenchymal and intravascular neutrophils. So, MLN 4924 treatment not only inhibits the NAE but also reduces the infiltration of these neutrophils but also maintains the integrity of the blood-brain barrier by upregulating the NF1. So this option can be considered as the therapeutic approach for the treatment of ischemic stroke.

As we discussed above that due to the dysregulation of protein degradation, cancer cells become drug resistant. This dysregulation of the protein degradation is associated with the dysregulation of NEDDylation. Studies showed that this mechanism also contributed to the progression of hepatocellular carcinomas.  It is considered that the upregulation of the NEDDylation, along with the downregulation of NEDD8 and NAE1 are the main causes of the poor prognosis of patients which are suffered from hepatocellular carcinoma.  Sorafenib  is considered the standard care for patients suffering from HCC although it does not have antitumor activity. Previously published studies give the clue that the treatment with MLN 4924 increases the sensitization of the hepatocellular carcinoma cells for Sorafenib. However, the present study stated that the treatment of HCC cells with the MLN 4924, significantly inhibits the progression and proliferation of the HCC by inhibiting the NAE1. This treatment also has the potential to decrease the migration capacity of the cancer cells along with an increase in the rate of apoptosis and reduced clonogenic survival. They found that the combined therapy of Sorafenib and MLN 4924 at a very less concentration, can decrease the survivability of the cancer cells by an increase in apoptosis. An in-vivo study conducted on the xenografts of the model of mice stated that the MLN 4924 increased the antitumor activity of the Sorafenib by increasing the expression of cullin-RING E3 CLR/Skp1- cullin1-F box E3 ubiquitin ligases substrates (IkB alpha, deptor, and p27,21). Thus it acts as an additive effect in the therapy of HCC.