What are MDM2 inhibitors?
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 .
Does MDM2 inhibit p53?
MDM2 inhibits p53 transcriptional activity, favours its nuclear export and stimulates its degradation, so inhibiting the p53–MDM2 interaction with synthetic molecules should lead to p53-mediated cell-cycle arrest or apoptosis in p53-positive stressed cells.
Is p53 an inhibitory?
Santa Cruz Biotechnology now offers a broad range of p53 Inhibitors. p53 is a DNA-binding tumor suppressor, which upregulates growth arrest and apoptosis-related genes in response to stress signals, thereby influencing programmed cell death, cell differentiation and cell cycle control mechanisms.
How does Apr 246 work?
In addition to targeting mutant p53, APR-246 inhibits the selenoprotein thioredoxin reductase 1 (TrxR1) and converts it to an active oxidase19, and depletes cellular gluthatione (GSH)20,21,22. This induces reactive oxygen species (ROS) and presumably contributes to the anticancer effect of APR-24623.
What does MDM2 stand for?
The MDM2 protein encoded by the mouse double minute 2 (MDM2) gene is the primary negative regulatory factor of the p53 protein. MDM2 can ligate the p53 protein via its E3 ubiquitin ligase, and the ubiquitinated p53 can be transferred to the cytoplasm and degraded by proteasomes.
What is MDM2 amplification?
MDM2 amplification by FISH is designed to detect amplification of the MDM2 gene to aid in patient diagnosis of soft tissue and bone tumors. In soft tissue tumors, MDM2 amplification is a frequent and specific finding in well differentiated liposarcoma/atypical lipomatous tumor (ref.
Is MDM2 a tumor suppressor?
The key target of Mdm2 is the p53 tumor suppressor. Mdm2 has been identified as a p53 interacting protein that represses p53 transcriptional activity. Mdm2 achieves this repression by binding to and blocking the N-terminal trans-activation domain of p53.
How does MDM2 control 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.
How is p53 inhibited?
The apoptosis-inducing activity of p53 can also be inhibited by inducing degradation of the p53 protein by cellular or viral proteins such as mdm-2 (34), HPV E6 (35), and adenovirus E1B55 and E4orf6 (36) or by compounds such as the NAD(P)H oxidoreductase 1 inhibitor dicoumarol and hsp90 inhibitors (9–11).
What is Magrolimab?
A humanized monoclonal antibody targeting the human cell surface antigen CD47, with potential immunostimulating and antineoplastic activities.
Are there any Mdm2 inhibitors in clinical trials?
We provide an overview of MDM2 inhibitors under preclinical and clinical investigation, with a focus on molecules with ongoing clinical trials, as indicated by ClinicalTrials.gov. Because preclinical and clinical exploration of combination strategies is underway, data supporting these combinations are also described.
What is the role of the MDM2 gene?
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 ].
Are there any small molecules that disrupt Mdm2?
Development of small molecules disrupting the MDM2–P53 interactions has been highly pursued from academia to industry in recent years 5, 9, 10, 11, 12, 13, 14.
How are Mdm2 and p53 peptides used in clinical trials?
MDM2 inhibitors in clinical trials. The core scaffolds are highlighted in blue. The P53 peptide and MDM2 protein are shown in green and gray surface, respectively. Adapted with permission from Ref. 5.