Drugs Targeting Dysfunctional wtp53 in AML
| Drugs . | Targeted inactivating mechanisms . | Mechanism of action and comments . | AML studies . | Reference . |
|---|---|---|---|---|
| MDM2 inhibitors | MDM2 upregulation | Inhibit MDM2–p53 interaction, thus promoting p53 stabilization and activation. Efficacy depends on p53 protein/network normalcy. Warning: MDM2 inhibition has the potential to increase the levels of GOF mutp53. | 13 | |
| Nutlins and other sm | The prototype MDM2 antagonists which disrupt wtp53-MDM2 interaction, by binding MDM2 in the p53-binding pocket | No | 13 | |
| Nutlin 3 (sm) (cis-imidazoline) | A research model molecule. Also disrupts the MDM2-p73/E2Fl interaction, thus promoting p53 - independent apoptosis and differentiation. Efficacy in AML is closely related to multiple synergistic interactions with doxorubicin, cytarabine, valproate, AZD6244 (RAF/MEK/ERK inhibitor), PI-103 (PI3/AKT/mTOR inhibitor), sorafenib (FLT3 inhibitor), MK-0457 (pan-Aurora kinase inhibitor), XIAP antisense oligonucleotide (XIAP inhibitor), and ABT-737 (BcL-2 inhibitor). Warning: acquisition of mutp53 in response to Nutlin 3 has been reported in cancer cells. | 13, 107, 111, 119, 120 | ||
| RG7112 (RO5045337) (Nutlin type) | Preliminary clinical trial data (supplemental Table 2) | Yes | 101 | |
| www.clinicaltrials.gov #NCT00623870 | ||||
| NCT01635296 | ||||
| RG7388, RO5503781 Idasanutlin (pyrrolidine class) | Preliminary clinical trial data (supplemental Table 2) | Yes | ||
| www.clinicaltrials.gov #NCT01773408 | ||||
| www.clinicaltrials.gov #NCT02545283 | ||||
| www.clinicaltrials.gov #NCT02670044 | ||||
| RG7775, R06839921 (Pegylated prodrug of Idasanutlin) | Preliminary clinical trial data (unpresented) | Yes | www.clinicaltrials.gov #NCT02098967 | |
| HDM201 (imidazolopyrrolidinone analog) | Preliminary clinical trial data (unpresented) | Yes | www.clinicaltrials.gov #NCT02143635, 121 | |
| AMG 232 (piperidinone) | Preliminary clinical trial data (unpresented) | Yes | www.clinicaltrials.gov #NCT02016729 | |
| www.clinicaltrials.gov #NCT03041688 | ||||
| MK-8242 (sm)* | Preliminary clinical trial data (supplemental Table 2) | Yes | www.clinicaltrials.gov #NCT01451437 | |
| DS-3032b (imidazothiazole) | Preliminary clinical trial data (supplemental Table 2) | Yes | www.clinicaltrials.gov #NCT02319369, 122 | |
| Stapled p53 peptidesALRN-6924 | MDM2/4 upregulation | Dual inhibition of MDM2 and MDM4 and escape resistance to MDM2 inhibition due to upregulated MDM4 | Yes | 13www.clinicaltrials.gov #NCT02909972 |
| RNA Pol I inhibitors | Trigger “nucleolar stress,” yielding p53 activation (which further promotes Pol I repression via inhibition of UBF-SL1 interaction); although wtp53 AML cells are most sensitive to Pol I inhibition, in the face of wtp53 dysfunction, this sensitivity should be reassessed | Yes | 123 | |
| CX-5461 | ACTRN12613001061729† | |||
| HDAC inhibitors | wtp53 de-acetylation (due to overexpressed or aberrantly recruited HDACs) | Acetylation is mutually exclusive with ubiquitylation; reacetylation reactivates wtp53 and sensitizes leukemic cells to MDM2 inhibitors, TKIs, and chemotherapy | Yes | 74, 84 |
| Valproic acid and entinostat (HDAC class l inhibitors) | www.clinicaltrials.gov #NCT00339196 and #NCT01305499 | |||
| Vorinostat and panobinostat (pan-HDAC inhibitors) | Yes | www.clinicaltrials.gov #NCT00948064 and #NCT01613976 | ||
| Tenovin 6 SIRT1/2 (HDAC class III) inhibitor | Research molecule | No | 124 | |
| SIRT1/2 inhibitors | Under development; although FLT3-ITD AML cells are sensitive to SIRT1 inhibitors, their efficacy might be limited as FLT3-ITD is considered a cooperating event in AML | No | 124 | |
| SINEs | CRM1 overexpression | Inhibit the CRM1 exporter; redirect wtp53 to the nucleus, thus promoting its transcriptional activities | 100 | |
| KPT-185 | KPT-185 also affects p53 by synergizing with Nutlin 3 in p53 nuclear retention, promoting NPMlc+ nucleolar relocalization and downregulating FLT3 expression | No | ||
| Selinexor (KPT-330) | Yes | www.clinicaltrials.gov #NCT02403310, #NCT02093403, #NCT02088541, #NCT02299518, #NCT02530476, #NCT02485535, and #NCT02573363 |
| Drugs . | Targeted inactivating mechanisms . | Mechanism of action and comments . | AML studies . | Reference . |
|---|---|---|---|---|
| MDM2 inhibitors | MDM2 upregulation | Inhibit MDM2–p53 interaction, thus promoting p53 stabilization and activation. Efficacy depends on p53 protein/network normalcy. Warning: MDM2 inhibition has the potential to increase the levels of GOF mutp53. | 13 | |
| Nutlins and other sm | The prototype MDM2 antagonists which disrupt wtp53-MDM2 interaction, by binding MDM2 in the p53-binding pocket | No | 13 | |
| Nutlin 3 (sm) (cis-imidazoline) | A research model molecule. Also disrupts the MDM2-p73/E2Fl interaction, thus promoting p53 - independent apoptosis and differentiation. Efficacy in AML is closely related to multiple synergistic interactions with doxorubicin, cytarabine, valproate, AZD6244 (RAF/MEK/ERK inhibitor), PI-103 (PI3/AKT/mTOR inhibitor), sorafenib (FLT3 inhibitor), MK-0457 (pan-Aurora kinase inhibitor), XIAP antisense oligonucleotide (XIAP inhibitor), and ABT-737 (BcL-2 inhibitor). Warning: acquisition of mutp53 in response to Nutlin 3 has been reported in cancer cells. | 13, 107, 111, 119, 120 | ||
| RG7112 (RO5045337) (Nutlin type) | Preliminary clinical trial data (supplemental Table 2) | Yes | 101 | |
| www.clinicaltrials.gov #NCT00623870 | ||||
| NCT01635296 | ||||
| RG7388, RO5503781 Idasanutlin (pyrrolidine class) | Preliminary clinical trial data (supplemental Table 2) | Yes | ||
| www.clinicaltrials.gov #NCT01773408 | ||||
| www.clinicaltrials.gov #NCT02545283 | ||||
| www.clinicaltrials.gov #NCT02670044 | ||||
| RG7775, R06839921 (Pegylated prodrug of Idasanutlin) | Preliminary clinical trial data (unpresented) | Yes | www.clinicaltrials.gov #NCT02098967 | |
| HDM201 (imidazolopyrrolidinone analog) | Preliminary clinical trial data (unpresented) | Yes | www.clinicaltrials.gov #NCT02143635, 121 | |
| AMG 232 (piperidinone) | Preliminary clinical trial data (unpresented) | Yes | www.clinicaltrials.gov #NCT02016729 | |
| www.clinicaltrials.gov #NCT03041688 | ||||
| MK-8242 (sm)* | Preliminary clinical trial data (supplemental Table 2) | Yes | www.clinicaltrials.gov #NCT01451437 | |
| DS-3032b (imidazothiazole) | Preliminary clinical trial data (supplemental Table 2) | Yes | www.clinicaltrials.gov #NCT02319369, 122 | |
| Stapled p53 peptidesALRN-6924 | MDM2/4 upregulation | Dual inhibition of MDM2 and MDM4 and escape resistance to MDM2 inhibition due to upregulated MDM4 | Yes | 13www.clinicaltrials.gov #NCT02909972 |
| RNA Pol I inhibitors | Trigger “nucleolar stress,” yielding p53 activation (which further promotes Pol I repression via inhibition of UBF-SL1 interaction); although wtp53 AML cells are most sensitive to Pol I inhibition, in the face of wtp53 dysfunction, this sensitivity should be reassessed | Yes | 123 | |
| CX-5461 | ACTRN12613001061729† | |||
| HDAC inhibitors | wtp53 de-acetylation (due to overexpressed or aberrantly recruited HDACs) | Acetylation is mutually exclusive with ubiquitylation; reacetylation reactivates wtp53 and sensitizes leukemic cells to MDM2 inhibitors, TKIs, and chemotherapy | Yes | 74, 84 |
| Valproic acid and entinostat (HDAC class l inhibitors) | www.clinicaltrials.gov #NCT00339196 and #NCT01305499 | |||
| Vorinostat and panobinostat (pan-HDAC inhibitors) | Yes | www.clinicaltrials.gov #NCT00948064 and #NCT01613976 | ||
| Tenovin 6 SIRT1/2 (HDAC class III) inhibitor | Research molecule | No | 124 | |
| SIRT1/2 inhibitors | Under development; although FLT3-ITD AML cells are sensitive to SIRT1 inhibitors, their efficacy might be limited as FLT3-ITD is considered a cooperating event in AML | No | 124 | |
| SINEs | CRM1 overexpression | Inhibit the CRM1 exporter; redirect wtp53 to the nucleus, thus promoting its transcriptional activities | 100 | |
| KPT-185 | KPT-185 also affects p53 by synergizing with Nutlin 3 in p53 nuclear retention, promoting NPMlc+ nucleolar relocalization and downregulating FLT3 expression | No | ||
| Selinexor (KPT-330) | Yes | www.clinicaltrials.gov #NCT02403310, #NCT02093403, #NCT02088541, #NCT02299518, #NCT02530476, #NCT02485535, and #NCT02573363 |
The referred clinical trials were evaluated as to the treatment effects on AML, but not necessarily with respect to p53 status.
sm, small molecules; SINEs, selective inhibitors of nuclear export; TKIs, tyrosine kinases inhibitors; UBF-SL1, upstream binding factor-selectivity factor 1
Chemical structure has not been disclosed regarding MK-8242.
Australian New Zealand Clinical Trials Registry trial ID.