Types of MDM2 inhibitors and mutant p53 binders, mechanisms of action, and toxicity
| Types of MDM2 inhibitors . | Examples . | Specific mechanisms of action . | Toxicity . | References . |
|---|---|---|---|---|
| Inhibitors of the p53-MDM2 interaction | RG7112, idasanutlin (RG7388), siremadlin (HDM201), and NVP-CGM097, APG-115 | These drugs combine with MDM2 to inhibit the p53-MDM2 interaction | GI toxicity and hematotoxicity | RG711254, RG738855, HDM20156, NVP-CGM09757 APG-11558 |
| Direct inductors of p53; plus: AMG-232 inhibits p53-MDM2 interaction | MK-8242 KRT-232 (AMG-232; navtemadlin) | This class of drugs acts directly on p53. They cause induction of p53 signaling | GI toxicity and hematotoxicity | AMG-23259 |
| Inhibitor of the p53-MDM2 interaction | Milademetan (DS-3032b/RAIN-32) | This class of drugs acts directly on p53 leading to p53 stabilization | GI toxicity and hematotoxicity | Milademetan (DS-3032b)60 |
| Mutant p53 binder, restores wt conformation | APR-246 (PRIMA-1(MET)) | Acts directly on mutant p53, restoring features of wt p53 | Fatigue, headache, dizziness, and other neurologic AEs | APR-246 (PRIMA-1(MET))61 |
| COTI-2 | Acts in wt and mutant p53 cancer; also inhibits the mTOR pathway | Nausea, vomiting, fatigue, and abdominal pain | NCT02433626 |
| Types of MDM2 inhibitors . | Examples . | Specific mechanisms of action . | Toxicity . | References . |
|---|---|---|---|---|
| Inhibitors of the p53-MDM2 interaction | RG7112, idasanutlin (RG7388), siremadlin (HDM201), and NVP-CGM097, APG-115 | These drugs combine with MDM2 to inhibit the p53-MDM2 interaction | GI toxicity and hematotoxicity | RG711254, RG738855, HDM20156, NVP-CGM09757 APG-11558 |
| Direct inductors of p53; plus: AMG-232 inhibits p53-MDM2 interaction | MK-8242 KRT-232 (AMG-232; navtemadlin) | This class of drugs acts directly on p53. They cause induction of p53 signaling | GI toxicity and hematotoxicity | AMG-23259 |
| Inhibitor of the p53-MDM2 interaction | Milademetan (DS-3032b/RAIN-32) | This class of drugs acts directly on p53 leading to p53 stabilization | GI toxicity and hematotoxicity | Milademetan (DS-3032b)60 |
| Mutant p53 binder, restores wt conformation | APR-246 (PRIMA-1(MET)) | Acts directly on mutant p53, restoring features of wt p53 | Fatigue, headache, dizziness, and other neurologic AEs | APR-246 (PRIMA-1(MET))61 |
| COTI-2 | Acts in wt and mutant p53 cancer; also inhibits the mTOR pathway | Nausea, vomiting, fatigue, and abdominal pain | NCT02433626 |
AEs, adverse events; GI, gastrointestinal; wt, wild-type.