P53's good partner MDM2, a potential heavy target?

P53.
The popularity in the field of oncology is definitely in the first echelon.
Although there are still no drugs on the market, it does not affect the enthusiasm of researchers for it
.

So, as a good partner of P53, will MDM2 become a potential heavy target? What forces have been put into it at home and abroad? Please see this manuscript
.

I have to say the tumor suppressor gene "P53"

P53.
It can be said that it is an extremely hot target in the field of oncology, and it is also a highly controversial target
.

Under physiological conditions, the expression level of P53 protein is very low and dynamic; after cells are stimulated, phosphorylated P53 dissociates from the MDM2/MDMX complex, and the protein level rises and activates; the sustained high level of P53 leads to The transcription of apoptosis-related genes such as PUMA and BAX triggers cell apoptosis, thereby inhibiting the occurrence of tumors
.

Figure 1.
1 P53 signaling pathway (very highly correlated with MDM2) (Source: BBA-Reviews on Cancer 1876 (2021) 188556)

MDM2 target characteristics

Among the many negative feedback regulation mechanisms of P53, the core mechanism is realized by MDM2 and its homo-heteromeric complex protein MDMX; MDM2 can inhibit the transcriptional activity and stability of P53.
At the same time, MDM2 is the target gene of P53, and the expression level is affected by P53.
Regulation
.

Structurally, the N-terminal P53 binding domain of MDM2 can bind to the transcription activation domain of P53, hindering the binding of P53 and its co-transcription activator, and inhibiting the activation of P53 target genes; on the other hand, the C-terminal RING (Really Interesting The New Gene) domain has E3 ubiquitin ligase activity, which can degrade P53 and MDMX by ubiquitination, and it can also be ubiquitinated
.

Figure 2.
1 MDM2/MDMX multi-dimensional control P53 stability (picture source: FEBS Letters 586 (2012) 1390–1396)

Global clinical research drugs

Nutlins3a is the first small molecule MDM2 inhibitor that has been proven to effectively inhibit the interaction between P53 and MDM2.
The basic structure is a multi-substituted dihydroimidazole.
The hydrophobic substituent on the dihydroimidazole ring can mimic the N-terminus of P53 and MDM2.
The key hydrophobic residue for binding
.

Figure 3.

The first P53-MDM2 protein-protein interaction inhibitor to enter clinical research was developed by Roche Pharmaceuticals, RG7112.

Other varieties: such as AMG-232.

Domestic patent application

Aiming at the target of MDM2, the types of applicants applying for related patents in China are enterprises with the largest proportion of more than 80%, followed by universities, and then research institutions and individuals

Enterprises, foreign MDM2 inhibitors of the layout of the main business of Novartis shares, Hoffmann-La Roche, Hoffman - Laroche, United States Amgen, Daiichi Sankyo and so on

In China, there are not many pharmaceutical companies currently deploying this target, mainly including Jiangsu Shenlang Biology, Yasheng Pharmaceutical, Nanjing Mingde New Drug, and Shanghai Changsen Pharmaceutical

references:

1.

3.
European Journal of Medicinal Chemistry.
doi.
org/10.
1016/j.
ejmech.
2019.
05.
018.

4.
State Intellectual Property Office