Drugs targeting mutp53 in AML
| . | Drug targets . | Mechanism of action and comments . | AML studies . | Reference . |
|---|---|---|---|---|
| Reconforming and reactivating drugs | ||||
| PRIMA-1MET (APR-246) | Various mutp53 (eg, R273H, R175H) | Converts to MQ, which binds to mutp53 core domain cysteines, thus restoring p53 DNA-binding and apoptosis; induces ROS formation, which augments the cell-death effect | Yes | 12, 104, 105 |
| PK7088/PhiKan083 and other novel Y220C targeting compounds | Y220C (rare in AML, might precede t-AML) | Binds to the mutation-induced surface crevice of mutp53 and stabilizes it; triggers BAX nuclear export to the mitochondria, thus restoring p53 nontranscriptional apoptosis | Preclinical | 115, 20 |
| NSC319726 (ZMC1) | R175H non–zinc binding and other mutp53 with impaired zinc binding | Zinc chelator, providing optimal zinc concentration for mutp53 proper folding; induces ROS formation | Preclinical | 103 |
| Reactivating peptides | Various mutp53 | Bind to the wtp53 conformation of the mutp53 protein, thus shifting the balance toward the wtp53 conformation | Preclinical | 102 |
| Drugsabrogating mutp53 GOF (to be added to RAD) | ||||
| HSP90 inhibitorsTanespimycin (geldanamycin derivative)Ganetespib | mutp53-HSP90 binding | Bind directly with high affinity to the tumor HSP90 ATP-binding pocket; promote MDM2/CHIP E3 ligases-mediated mutp53 degradation; inhibit PI3K-AKT and NF-κB signaling | YesYes | 43, 44, 116www.clinicaltrials.gov #NCT00098423www.clinicaltrials.gov #NCT00858572 |
| Vorinostat HDAC6 inhibitor | Inhibits HSP90 deacetylation and activity | Yes | www.clinicaltrials.gov #NCT00948064 | |
| RETRA | mutp53-p73 binding | Disrupts mutp53-p73 interaction; increases p73 levels; restores p73-mediated expression of p53 target genes (provided p73 is not dysfunctional due to p73 promoter methylation, or aberrant TAp73/ΔNp73 ratio) | Preclinical | 111, 112 |
| MDR modulators: fourth-generation MDR reversal agents and PRIMA-1MET(APR-246) | mutp53-induced MDR1 transactivation | Currently existing MDR1 inhibitors have failed clinically because of systemic toxicity or inefficiency; mutp53 reactivation has an added effect on MDR1 upregulation since wtp53 represses MDRl promoter activity | Preclinical | 47, 113, 117 |
| NF-κB inhibitorsBortezomib proteasome inhibitor | mutp53-mediated NFκB activation (TNFα-induced) and mutp53–NF-κB functional synergism | Inhibit NF-κB nuclear translocation and activity. Selectively target LSCs (in which NF-κB activity is aberrantly increased compared with normal HPSCs). Since NF-κB also enhances MDR1, its inhibition might also address chemoresistance. Beware: full reactivation of mutp53 should precede proteasome-inhibitor treatment | Yes | 50, 51, 118 50 |
| . | Drug targets . | Mechanism of action and comments . | AML studies . | Reference . |
|---|---|---|---|---|
| Reconforming and reactivating drugs | ||||
| PRIMA-1MET (APR-246) | Various mutp53 (eg, R273H, R175H) | Converts to MQ, which binds to mutp53 core domain cysteines, thus restoring p53 DNA-binding and apoptosis; induces ROS formation, which augments the cell-death effect | Yes | 12, 104, 105 |
| PK7088/PhiKan083 and other novel Y220C targeting compounds | Y220C (rare in AML, might precede t-AML) | Binds to the mutation-induced surface crevice of mutp53 and stabilizes it; triggers BAX nuclear export to the mitochondria, thus restoring p53 nontranscriptional apoptosis | Preclinical | 115, 20 |
| NSC319726 (ZMC1) | R175H non–zinc binding and other mutp53 with impaired zinc binding | Zinc chelator, providing optimal zinc concentration for mutp53 proper folding; induces ROS formation | Preclinical | 103 |
| Reactivating peptides | Various mutp53 | Bind to the wtp53 conformation of the mutp53 protein, thus shifting the balance toward the wtp53 conformation | Preclinical | 102 |
| Drugsabrogating mutp53 GOF (to be added to RAD) | ||||
| HSP90 inhibitorsTanespimycin (geldanamycin derivative)Ganetespib | mutp53-HSP90 binding | Bind directly with high affinity to the tumor HSP90 ATP-binding pocket; promote MDM2/CHIP E3 ligases-mediated mutp53 degradation; inhibit PI3K-AKT and NF-κB signaling | YesYes | 43, 44, 116www.clinicaltrials.gov #NCT00098423www.clinicaltrials.gov #NCT00858572 |
| Vorinostat HDAC6 inhibitor | Inhibits HSP90 deacetylation and activity | Yes | www.clinicaltrials.gov #NCT00948064 | |
| RETRA | mutp53-p73 binding | Disrupts mutp53-p73 interaction; increases p73 levels; restores p73-mediated expression of p53 target genes (provided p73 is not dysfunctional due to p73 promoter methylation, or aberrant TAp73/ΔNp73 ratio) | Preclinical | 111, 112 |
| MDR modulators: fourth-generation MDR reversal agents and PRIMA-1MET(APR-246) | mutp53-induced MDR1 transactivation | Currently existing MDR1 inhibitors have failed clinically because of systemic toxicity or inefficiency; mutp53 reactivation has an added effect on MDR1 upregulation since wtp53 represses MDRl promoter activity | Preclinical | 47, 113, 117 |
| NF-κB inhibitorsBortezomib proteasome inhibitor | mutp53-mediated NFκB activation (TNFα-induced) and mutp53–NF-κB functional synergism | Inhibit NF-κB nuclear translocation and activity. Selectively target LSCs (in which NF-κB activity is aberrantly increased compared with normal HPSCs). Since NF-κB also enhances MDR1, its inhibition might also address chemoresistance. Beware: full reactivation of mutp53 should precede proteasome-inhibitor treatment | Yes | 50, 51, 118 50 |
The referred clinical trials evaluated the drugs’ therapeutic efficacy in AML, but not necessarily in view of p53 status.
MQ, methylene quinuclidinone; RAD, reactivating drug; RETRA, reactivation of transcriptional reporter activity; ROS, reactive oxygen species.