State of the Art of Pharmacological Activators of p53 in Ocular Malignancies
Abstract
:Simple Summary
Abstract
1. Introduction
2. The Role of p53 in Tissue and Ocular Homeostasis
3. Pharmacological Activators of the p53 Pathway
4. Role of p53 Therapy in Pterygium
5. Role of p53 Therapy in Conjunctival Melanoma
6. Role of p53 Therapy for Retinoblastoma
7. Role of p53 in Uveal Melanoma
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Conditions | Phases, N | Status | NCT Number |
---|---|---|---|---|
Idasanutlin (RG7388, RO5503781) | ||||
PV | II, 27 | Terminated | NCT03287245 | |
PV, ET | I, 13 | Completed | NCT02407080 | |
AML | I/II, 24 | Terminated | NCT03850535 | |
AML | I, 88 | Completed | NCT02670044 | |
AML | III, 447 | Terminated | NCT02545283 | |
AML, Acute Lymphoblastic Leukemia, Neuroblastoma | I/II, 183 | Recruiting | NCT04029688 | |
AML | I, 122 | Completed | NCT01773408 | |
NHL | I/II, 25 | Terminated | NCT02624986 | |
NHL | I/II, 29 | Terminated | NCT03135262 | |
Recurrent Plasma Cell Myeloma | I/II, 33 | Active, not recruiting | NCT02633059 | |
CC | I/II, 94 | Terminated | NCT03555149 | |
BC | I/II, 12 | Terminated | NCT03566485 | |
ST | I, 8 | Completed | NCT02828930 | |
ST | I, 48 | Completed | NCT03362723 | |
ST | II, 770 | Recruiting | NCT04589845 | |
GB | I/II, 350 | Recruiting | NCT03158389 | |
ST | I, 99 | Completed | NCT01462175 | |
ST | I, 61 | Completed | NCT01901172 | |
Nutlin (RO5045337, RG7112) | ||||
PV, ET | n.a., 131 | Completed | NCT01970930 | |
AML | I, 43 | Completed | NCT01635296 | |
Hematologic Cancers | I, 116 | Completed | NCT00623870 | |
AML | I, 11 | Completed | NCT01677780 | |
Sarcoma | I, 23 | Completed | NCT01605526 | |
Sarcoma | I, 20 | Completed | NCT01143740 | |
ST | I, 76 | Completed | NCT01164033 | |
ST | I, 106 | Completed | NCT00559533 | |
Alrizomadlin (APG-115) | ||||
T-Prolymphocytic Leukemia | II, 36 | Recruiting | NCT04496349 | |
AML, Chronic Myelomonocytic Leukemia, MDS | I/II, 69 | Recruiting | NCT04358393 | |
AML, MDS | I, 102 | Recruiting | NCT04275518 | |
Lymphoma, ST | I, 50 | Completed | NCT02935907 | |
Neuroblastoma, ST | I, 100 | Recruiting | NCT05701306 | |
Liposarcoma, ST | I/II, 92 | Recruiting | NCT04785196 | |
Uveal Melanoma, Melanoma, ST | I/II, 224 | Recruiting | NCT03611868 | |
Salivary Gland Cancer | I/II, 34 | Recruiting | NCT03781986 | |
SAR405838 (MI-77301) | ||||
ST | I, 26 | Completed | NCT01985191 | |
ST | I, 77 | Completed | NCT01636479 | |
MK-8242 | ||||
AML | I, 26 | Terminated | NCT01451437 | |
ST | I, 48 | Terminated | NCT01463696 | |
Kevetrin | ||||
Ovarian Cancer | II, 2 | Completed | NCT03042702 | |
ST | I, 48 | Completed | NCT01664000 | |
Sulanemadlin (ALRN-6924) | ||||
BC | I, 6 | Terminated | NCT05622058 | |
AML, MDS | I, 55 | Completed | NCT02909972 | |
BC, ST | I, 35 | Active, not recruiting | NCT03725436 | |
Retinoblastoma, Leukemia, Lymphoma, Brain Tumor, ST | I, 69 | Active, not recruiting | NCT03654716 | |
Lymphoma, ST | I/II, 149 | Completed | NCT02264613 | |
Lung Cancer | I, 35 | Terminated | NCT04022876 | |
Siremadlin (HDM201) | ||||
Hepatic Impairment | I, 48 | Recruiting | NCT05599932 | |
AML, Allogeneic Stem Cell Transplantation | I/II, 38 | Recruiting | NCT05447663 | |
Sarcoma | I/II, 58 | Recruiting | NCT05180695 | |
AML | I, 2 | Terminated | NCT04496999 | |
CC, ST | I, 24 | Recruiting | NCT03714958 | |
Liposarcoma | I, 74 | Completed | NCT02343172 | |
AML | I/II, 56 | Recruiting | NCT05155709 | |
ST | I, 208 | Completed | NCT02143635 | |
AML, MDS | I, 52 | Active, not recruiting | NCT03940352 | |
AML | I/II, 0 | Withdrawn | NCT03760445 | |
Uveal Melanoma | I, 107 | Terminated | NCT02601378 | |
Myelofibrosis | I/II, 45 | Active, not recruiting | NCT04097821 | |
ST | II, 425 | Recruiting | NCT04116541 | |
CC, Lung Cancer, BC, Renal Cell Carcinoma | I, 298 | Completed | NCT02890069 | |
Milademetan (RAIN-32, DS-3032) | ||||
AML | I, 14 | Completed | NCT03671564 | |
AML | I, 10 | Terminated | NCT03552029 | |
AML, Myelodysplastic Syndrome | I, 74 | Terminated | NCT02319369 | |
AML | I/II, 21 | Completed | NCT03634228 | |
Lymphoma, ST | I, 108 | Completed | NCT01877382 | |
ST | II, 65 | Recruiting | NCT05012397 | |
Liposarcoma | III, 160 | Active, not recruiting | NCT04979442 | |
CGM097 (NVP-CGM097) | ||||
ST | I, 51 | Completed | NCT01760525 | |
Navtemadlin (AMG-232, KRT-232) | ||||
AML | I/II, 18 | Active, not recruiting | NCT04669067 | |
AML | I, 48 | Suspended | NCT03041688 | |
AML | I, 36 | Completed | NCT02016729 | |
AML | I, 24 | Suspended | NCT04190550 | |
AML | I/II, 86 | Recruiting | NCT04113616 | |
Chronic Myeloid Leukemia | I/II, 109 | Recruiting | NCT04835584 | |
Chronic Lymphocytic Leukemia, NHL | I/II, 84 | Recruiting | NCT04502394 | |
PM, PV, ET | I/II, 116 | Recruiting | NCT04640532 | |
PM, PV, ET | II, 52 | Recruiting | NCT04878003 | |
PM, PV, ET | II/III, 385 | Recruiting | NCT03662126 | |
Myelofibrosis | I/II, 36 | Recruiting | NCT04485260 | |
PV | II, 20 | Unknown status | NCT03669965 | |
Plasma Cell Myeloma | I, 40 | Recruiting | NCT03031730 | |
GB, Multiple Myeloma, ST | I, 107 | Completed | NCT01723020 | |
Small cell Lung Cancer | II, 38 | Recruiting | NCT05027867 | |
Non Small Lung Cancer | I/II, 92 | Not yet recruiting | NCT05705466 | |
Merkel Cell Carcinoma | I/II, 115 | Recruiting | NCT03787602 | |
GB, Gliosarcoma | I, 86 | Suspended | NCT03107780 | |
Melanoma, ST | I, 31 | Completed | NCT02110355 | |
Sarcoma | I, 46 | Active, not recruiting | NCT03217266 | |
Endometrial Cancer | II/III, 268 | Not yet recruiting | NCT05797831 |
Drugs | Synonyms | Molecular Formula | Molecular Weight (g/mol) | Mechanism of Action |
---|---|---|---|---|
Alrizomadlin | APG-115 | C34H38Cl2FN3O4 | 642.6 | Blocks HDM2 interaction with p53 |
CGM097 | NVP-CGM097 | C38H47ClN4O4 | 659.3 | Blocks HDM2 interaction with p53 |
Idasanutlin | RG7388, RO5503781 | C31H29Cl2F2N3O4 | 616.5 | Blocks MDM2 interaction with p53 |
Kevetrin | 4-Isothioureidobutyronitrile, thioureidobutyronitrile | C5H9N3S | 143.21 | Induce activation of p53; Alters the E3 ligase processivity of MDM2; Induces p21 and PUMA |
Milademetan | RAIN-32, DS-3032 | C30H34Cl2FN5O4 | 618.5 | Blocks MDM2 interaction with p53; Inhibits proteasome-mediated enzymatic degradation of p53; Restores p53 transcriptional activity and signaling |
MK-8242 | C41H47F6N3O7S | 839.9 | Blocks MDM2 interaction with p53; Restores p53 signaling | |
Navtemadlin | AMG-232, KRT-232 | C28H35Cl2NO5S | 568.6 | Blocks MDM2 interaction with p53; Restores p53 transcriptional activity |
RG7112 | RO5045337 | C38H48Cl2N4O4S | 727.8 | Blocks MDM2 interaction with p53; Stabilizes the p53 protein; Induces p53 target genes such as CDKN1A, NOXA, PUMA, Fas, and BAX |
SAR405838 | MI-77301 | C29H34Cl2FN3O3 | 562.5 | Blocks MDM2 interaction with p53; Inhibits proteasome-mediated enzymatic degradation of p53; Restores p53 transcriptional activity and signaling |
Siremadlin | HDM201 | C26H24Cl2N6O4 | 555.4 | Blocks MDM2 interaction with p53; Inhibits proteasome-mediated enzymatic degradation of p53; Restores p53 transcriptional activity and signaling |
Sulanemadlin | ALRN-6924 | C95H140N20O23 | 1930.2 | Blocks HDM2 interaction with p53 |
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Casciano, F.; Zauli, E.; Busin, M.; Caruso, L.; AlMesfer, S.; Al-Swailem, S.; Zauli, G.; Yu, A.C. State of the Art of Pharmacological Activators of p53 in Ocular Malignancies. Cancers 2023, 15, 3593. https://doi.org/10.3390/cancers15143593
Casciano F, Zauli E, Busin M, Caruso L, AlMesfer S, Al-Swailem S, Zauli G, Yu AC. State of the Art of Pharmacological Activators of p53 in Ocular Malignancies. Cancers. 2023; 15(14):3593. https://doi.org/10.3390/cancers15143593
Chicago/Turabian StyleCasciano, Fabio, Enrico Zauli, Massimo Busin, Lorenzo Caruso, Saleh AlMesfer, Samar Al-Swailem, Giorgio Zauli, and Angeli Christy Yu. 2023. "State of the Art of Pharmacological Activators of p53 in Ocular Malignancies" Cancers 15, no. 14: 3593. https://doi.org/10.3390/cancers15143593