What do Nutlins do?

Nutlins were the first hits identified to disrupt p53/MDM2 interactions potently and specifically (96). These compounds activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and tumor growth inhibition.

What does Nutlin-3 do?

Nutlin-3, a selective inhibitor of p53-murine double minute 2 (MDM2) interaction, exerted antitumor activity in a number of human malignancies [60, 61]. Nutlin-3 increased apoptosis and inhibited cell growth through the activation of the p53 pathway [62, 63].

What are MDM2 inhibitors?

The MDM2 gene codifies for an E3 ubiquitin ligase that acts as a powerful inhibitor of the tumor suppressor P53, the master regulator of the cell cycle progression, in a feedback loop that is attracting great interests and attention as a potential target for tumor therapeutic purposes [5].

How do MDM2 inhibitors work?

Both MDM2 and MDMX also inhibit the transcription activity of p73 tumor suppressor by associating with its N-terminus and inhibiting transcription activity (lower panel). The binding of MDM2 enables the binding of ITCH, E3 ubiquitin ligase of p73 and its proteasomal degradation.

How does Idasanutlin work?

Idasanutlin binds to MDM2 blocking the interaction between the MDM2 protein and the transcriptional activation domain of the tumor suppressor protein p53. By preventing the MDM2-p53 interaction, p53 is not enzymatically degraded and the transcriptional activity of p53 is restored.

How does MDM2 regulate p53?

MDM2 negatively regulates p53 by targeting the ubiquitin ligase activity of MDM2. A complementary approach to prevent p53 degradation by MDM2 is to develop agents designed to inhibit the E3 ligase activity of MDM2 directly so as to mimic the effects of ARF or the ribosomal protein L11.

What is the MDM2 protein?

Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. Mdm2 is an important negative regulator of the p53 tumor suppressor.

What happens if you inhibit p53?

The loss of p53 tumour-suppressor activity by mutation/deletion of TP53 or inhibition of p53 allows the proliferation of the cells that are damaged under the stress conditions. This uncontrolled proliferation can lead to tumour development.

How does MDM2 inactivate p53?

The increased MDM2 levels cause it, in turn, to bind and inactivate p53 by directly blocking the p53 transactivational domain and by targeting the p53 protein for ubiquitin-dependent degradation by the proteasome[72],[73] (Fig. 4).

Does p53 bind to MDM2?

MDM2 directly binds to the transactivation domain of p53 and inhibits its transcriptional activity, causes the ubiquitination and proteasomal degradation of p53, and exports p53 out of the nucleus which promotes p53 degradation and inhibits its activity.

What is RG7112?

RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. RG7112 binds MDM2 with high affinity (K (D) ~ 11 nmol/L), blocking its interactions with p53 in vitro.

What are the derivatives of Nutlin?

Several derivatives of nutlin, such as RG7112 and RG7388 ( Idasanutlin) have been developed and progressed into human studies. Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.

How does RG7112 bind to Mdm2?

RG7112 binds MDM2 with high affinity (K (D) ~ 11 nmol/L), blocking its interactions with p53 in vitro. A crystal structure of the RG7112-MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues.

Does rgrg7112 have antitumor activity?

RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varied widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, inhibition of caspase activity did not change the kinetics of p53-induced cell death.