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Table 3 Compounds that block MDM2-P53 interaction and reactivate TP53 gene

From: Exploring the multiple roles of guardian of the genome: P53

S. No. Name of the Compound Chemical name or class Mechanism References
1 Nutlin-3 (MDM2 antagonist) Cis-imidazoline Nutlin-3 is one of the compounds belonging to the class of Nutulins. It is an MDM2 antagonist that induces cell cycle arrest in rapidly proliferating cancer cells on G1 and G2 phases of the cell cycle. “In various cancer cell lines, nutlin-3 induces apoptosis and enhanced cisplatin-induced apoptosis through Fas death receptor pathway in cisplatin-resistant cells.” [216]
2 MI-219 (MDM2-P53 interaction inhibitor) Spiro-oxindole “MI-219 is a potent, highly selective, and orally active small-molecule inhibitor of the MDM2-P53 interaction”. “In cancer cells with wild-type P53, MI-219 disrupts MDM2-P53 interaction and activates the P53 pathway leading to cell cycle arrest and apoptosis in vitro and in vivo”. A similar effect of activating P53 in established tumour xenograft tissues resulted in cell cycle arrest and apoptosis. “Thus, MI-219 activates P53 in healthy tissues with minimal accumulation of P53. When used in combination with etoposide, MI-219-induced cytotoxicity was not affected by MDM2 knockdown or by an X-linked inhibitor of apoptosis protein (XIAP) inhibitor, suggesting MI-219 could act as a chemosensitizing agent”. [217, 218]
3 MI-319 (MDM2-P53 interaction inhibitor) Spiro-oxindole “MI-319 is an analogue closely related to MI-219 and Nutlin-3. Like MI-219, designed to target MDM2-P53 interaction, and it binds to MDM2 protein with a high affinity that is over 500-fold more potent than a natural P53 peptide”. Various studies have shown that MI-319, when used in combination with anticancer drug cisplatin, synergistically inhibited cell cycle growth and induced apoptosis in pancreatic cancer. [219]
4 HLI98 compounds 5-Deazaflavin “HLI98 family includes compounds that are strictly related to 7-nitro-5-deazaflavin and identified via high throughput screening of MDM2 autoubiquitinylation as inhibitors of MDM2 E3 ubiquitin ligase activity”. “5-Deazaflavin is a highly potent, water-soluble inhibitor of MDM2-mediated P53 ubiquitinylation with low micromolar cellular potency”. “It results in increased MDM2 and P53 protein levels, leading to selective P53-dependent apoptosis in various cancer cell lines with wild-type P53”. [220, 221]