Table 4. Approaches to target MDM2 and MDMX.
| Targeting approach | Compound | Class | Target | Proposed working mechanism | Remarks |
|---|---|---|---|---|---|
| Modulating protein expression | NSC207895 (Ref. 88) | Small molecule | MDMX | Inhibits MDMX transcription | Highly related to DNA damage agents89 |
| 17-AAG92 | Small molecule | HSP90 | HSP90 inhibitor | Destabilizes MDMX through an undefined mechanism92 | |
| Targeting protein–protein interaction | Nutlin 3a96 | Small molecule | MDM2 N-terminal p53-binding pocket | Disrupts p53–MDM2 interaction | The derivative, RG7112, is in Phase I clinical trial |
| MI-219 (Ref. 97) | Small molecule | MDM2 N-terminal p53-binding pocket | Disrupts p53–MDM2 interaction | Preclinical development | |
| SJ-172550 (Ref. 105) | Small molecule | MDMX N-terminal p53-binding pocket | Disrupts p53–MDMX interaction | Forms adducts with cysteine in MDM2 and MDMX106 | |
| RO-5963 (Ref. 103) | Small molecule | Both MDM2 and MDMX N-terminal p53-binding pocket | Disrupts p53–MDM2 and p53–MDMX interactions | Causes MDM2 and MDMX homodimers and heterodimers103 | |
| WK 298 (Ref. 173) | Small molecule | MDMX | Disrupts p53–MDMX interaction | No cellular activity173 | |
| AM-8553 (Ref. 174) | Small molecule | MDM2 N-terminal p53-binding pocket | Disrupts p53–MDM2 interaction | ||
| SAH-p53-8 (Ref. 110) | Peptidic compound | Both MDM2 and MDMX N-terminal p53-binding pocket | Disrupts p53–MDM2 and p53–MDMX interactions | Cellular uptake requires pinocytosis113 | |
| PMI peptide112 | Peptidic compound | Both MDM2 and MDMX N-terminal p53-binding pocket | Disrupts p53–MDM2 and p53–MDMX interactions | No cellular activity175 | |
| pDI peptide111 | Peptide | Both MDM2 and MDMX N-terminal p53-binding pocket | Disrupts p53–MDM2 and p53–MDMX interactions | Cellular activity only in context of adenoviral delivery111 | |
| RITA158 | Small molecule | p53 N-terminal domain | Disrupts p53–MDM2 interaction | Showed p53-independent activity161 | |
| Targeting E3 ubiquitin ligase activity | HLI98 (Ref. 115) | Small molecule | MDM2 | Inhibits MDM2 ubiquitin ligase activity | Showed p53-independent activity115 |
| MPD116 | Small molecule | MDM2 RING domain | Inhibits MDM2 ubiquitin ligase activity | Based on HLI compound. Potent derivative showed p53-independent activity116 | |
| MEL23 and MEL24 (Ref. 117) | Small molecule | MDM2 | Inhibits MDM2 ubiquitin ligase activity | ||
| Activating p53 via other mechanisms | JNJ-26854165 | Small molecule | MDM2 | Inhibits p53–MDM2–proteasome interaction | Showed p53-independent activity162 |
HSP90, heat shock protein 90; RITA, reactivation of p53 and induction of tumour cell apoptosis; SAH-p53-8, stabilized α-helix of p53 variant 8.