An important mediator of growth arrest, senescence, and apoptosis in response to a wide range of cellular damage is the tumor suppressor protein p53. In healthy cells, the short-lived protein p53 is kept at very low levels that are frequently undetectable. When under stress, the p53 protein builds up in the cell, binds to p53-response elements in its tetrameric form, and triggers the transcription of a number of genes.
P53 causes MDM-2 to become transcriptionally active, and MDM-2 then inhibits p53 activity in a number of ways. MDM-2 inhibits p53-mediated transactivation by attaching to the p53 transactivation domain. After binding to p53, MDM-2 induces nuclear export because it has a signal sequence that is similar to the nuclear export signal of several viral proteins. Because p53 is a transcription factor, MDM-2's transport of it to the cytoplasm prevents it from accessing the DNA, which is necessary for its function. Finally, because MDM-2 is an ubiquitin ligase, it can direct the proteasome to target p53 for destruction.
The overexpression of the negative regulators MDM2 and MDM4 or the diminished activity of the MDM2 inhibitor ARF both inactivate p53 in many tumors. In these tumors, small molecules that block the interaction of MDM2 and/or MDM4 with p53 can cause the pathway to be reactivated. Trials on such molecules are currently being conducted.
|A-1155463 (A1155463) is a novel highly potent and selective BCL-XL inhibitor with antitumor activity.
|A-1331852 (A1331852) is a potent and selective BCL-XL inhibitor with anticancer and immunomodulatory effects.
|Amifostine thiol (WR-1065)
|active metabolite of Amifostine, a cytoprotector
|BDA-366 (BDA366) is a potent andselective small-molecule antagonist of the Bcl2-BH4 domain with potential anticancer activity.
|Eprenetapopt (APR246; PRIMA-1MET)
|Eprenetapopt (APR-246; PRIMA-1MET), a methylated derivative of PRIMA-1 and a mutant p53 reactivator, is a novel and potent small molecule compoundthat is able to restore wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells.
|HDM201 (Siremadlin) HCl
|HDM201 HCl (also called Siremadlin;NVP-HDM201, HDM stands for human double minute 2 homolog) is an orally bioavailable, highly potent and selective inhibitor of the p53-Mdm2 protein-protein interaction.
|dual inhibitor of MDM2/XIAP
|MI-773 (2R,3S-isomer) (also known as MI773; SAR-405838; SAR405838), aspirooxindole analog, is a specific and orally bioavailable small molecule antagonist of MDM2-p53 protein‐protein interactionwith antitumor activity.
|MN58b (MN 58b bromide; MN58b; MN-58b) is a novel, potent and selective Choline kinase α (CHKα) inhibitor with anticancer activities.
|MX69 is a novel, potent and selective MDM2/XIAP dual inhibitorthat has the potential use for treatment of cancer.
|NSC 207895 is a novel anticancer agent that is able to suppress MDM2 with an IC50 of 2.5 μM, which leads to enhanced p53 stabilization/activation and DNA damage.
|Nutlin-3, a tetra-substituted imidazoline, is a novel potent and selective small-molecule antagonist/inhibitor of murine double minute 2 (MDM2) with potential antitumor activities.
|Nutlin-3a, the active enantiomer of Nutlin-3, is a novel and potent p53/MDM2 (murine double minute) protein protein interactioninhibitor with an IC50 of 90 nM in cell-free assays.
|Nutlin-3b, a less active/inactive isomer of nutlin-3, is a novel antagonist or inhibitor of p53/MDM2 (murine double minute 2) protein protein interactionwith IC50 value of 13.6 μM.
|NVP-CGM097 (also called CGM-097; CGM097; NVP-CGM-097; NVP CGM097)is a novel, highly potent,orally bioavailable and selective MDM2 ((human homolog of double minute 2) inhibitor with antitumor activity.
|NVP-CGM097 sulfate (CGM097; NVP-CGM-097; NVPCGM097), the sulfate salt ofNVP-CGM097 or CGM-097, is a novel, orally bioavailable and selective inhibitor of MDM2 (human homolog of double minute 2)-p53 interaction with antitumor activity.
|PD-1/PD-L1 Inhibitor 3
|PD-1/PD-L1 Inhibitor 3 is a macrocyclic inhibitor of PD-1/PD-L1 protein-protein interaction.
|PRIMA-1 [also known as Prima-1; chemcial name, 2,2-Bis(hydroxymethyl)-3-quinuclidinone], a novel and potent small molecule compound which is the active form ofAPR-246 (also known as PRIMA-1MET), is a mutant p53 reactivator which induces apoptosis and inhibits growth of human tumors.
|RG7112(also known as RO5045337) is a novel, potent and highly selective antagonist/inhibitor of thep53-MDM2 protein-protein interaction withIC50of 11 nM.
|RG7388 (also known asIdasanutlin;RG-7388;RO5503781) is a novel, potent and highly selective antagonist of thep53-MDM2 protein-protein interaction with potential antitumor activity.