The p53 tumor suppressor is a principal mediator of growth arrest, senescence, and apoptosis in response to a broad array of cellular damage. p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Under stress conditions, the p53 protein accumulates in the cell, binds in its tetrameric form to p53-response elements and induces the transcription of various genes.
MDM-2 is transcriptionally activated by p53 and MDM-2, in turn, inhibits p53 activity in several ways. MDM-2 binds to the p53 transactivation domain and thereby inhibits p53-mediated transactivation. MDM-2 also contains a signal sequence that is similar to the nuclear export signal of various viral proteins and, after binding to p53, it induces its nuclear export. As p53 is a transcription factor, it needs to be in the nucleus to be able to access the DNA; its transport to the cytoplasm by MDM-2 prevents this. Finally, MDM-2 is a ubiquitin ligase, so is able to target p53 for degradation by the proteasome.
In many tumors p53 is inactivated by the overexpression of the negative regulators MDM2 and MDM4 or by the loss of activity of the MDM2 inhibitor ARF. The pathway can be reactivated in these tumors by small molecules that inhibit the interaction of MDM2 and/or MDM4 with p53. Such molecules are now in clinical trials.
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HDM-201 (NVP-HDM 201, Siremadlin) is a highly potent p53-MDM2 interaction inhibitor with biochemical IC50 of 0.13 nM, cellular IC50 of 90 nM; a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.
AMG 232 is a potent, selective, orally bioavailable MDM2-p53 inhibitor with Kd of 0.045 nM, inhibits SJSA-1 cell proliferation with IC50 of 9.1 nM; robustly induces p53 activity, leading to cell-cycle arrest and inhibition of tumor cell proliferation; significantly inhibits tumor growth in SJSA-1 osteosarcoma xenograft model with ED50 of 9.1 mg/kg, also showsignificantly superior antitumor efficacy chombined with chemotherapies in vivo, enhances radiosensitivity via inhibition of damage repair signaling.
CB-002 is a novel small molecule that restores p53 function in mutant p53-expressing colorectal cancer cells without toxicity to normal human fibroblasts; increases expression of endogenous p53 target genes NOXA, DR5, and p21 and cell death; decreases the stability of mutant p53 in RXF393 cancer cells and an exogenously expressed R175H p53 mutant in HCT116 p53-null cells.
MB710 is a small-molecule p53 mutant Y220C stabilizer, binds tightly to the Y220C pocket and stabilizes p53-Y220C in vitro.
MB725 is a small-molecule p53 mutant Y220C stabilizer, induces selective viability reduction in several p53-Y220C cancer cell lines (Huh7 cell IC50=10 uM); reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediated transcriptional activation of the Y220C mutant.
A highly potent and selective, small-molecule p53-MDM2 inhibitor with HRFT IC50 of 5 nM; shows marked improvement in both in vitro and in vivo pharmacological properties.
COTI-2 (COTI2) is an orally available thiosemicarbazone that may act on mutant forms of p53 and PI3K/AKT/mTOR pathway; induces apoptosis in a wide variety of human tumor cells in culture (IC50s<40 nM), inhibits the proliferation of colorectal cancer cell lines more effectively than cetuximab and erlotinib; shows superior activity against tumor, and is safe and well-tolerated in vivo.
A sirtuin inhibitor that increases p53 levels in MCF-7 cells.
A novel specific inhibitor of MDM2 inhibitor with Kd of 2.75 uM; induces ubiquitination of endogenous MDM2, results in activation of p53 and inhibition of XIAP, and induces cell apoptosis and death in cancer cells; shows significant apoptotic and anti-proliferative effects on MDM2-expressing cancer cells both in vitro and in vivo, with minimal inhibitory effect on normal human hematopoiesis.
YH239-EE is the ethyl ester of YH239, which is a highly potent, selective MDM2-p53 antagonist with Ki of 300 nM, shows no affinity for MDM4; induces apoptosis in AML cells and patient samples, induces p53 and activates the apoptotic caspase 3/7 in MOLM-13 (wt-p53) cells.
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