Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials
Abstract
Simple Summary
Abstract
1. Introduction
2. Drugs Targeting p53 Mutations
2.1. Restoration or Stabilization of wtp53 Conformation from Missense mutp53
2.1.1. APR-246 (Eprenetapopt, PRIMA-1MET)
2.1.2. Phenethyl Isothiocyanate (PEITC)
2.1.3. Arsenic Trioxide (ATO/Trisenox)
2.1.4. Aminoglycosides to Rescue p53 Nonsense Mutations
2.2. Depletion or Degradation of mutp53 Protein
2.2.1. HSP90 Inhibitors (Ganetespib/STA-9090)
2.2.2. Statins (Atorvastatin)
2.2.3. ATO/Trisenox
2.2.4. Vorinostat (Zolinza/Suberoylanilide Hydroxamic Acid: SAHA)
2.3. Induction of p53 Synthetic Lethality or Targeting Vulnerabilities Imposed by p53 Mutations or Deletions
2.3.1. p53 Synthetic Lethality Induced by a Wee1 Inhibitor, Adavosertib (AZD1775/MK-1775)
2.3.2. Targeting the Reverse Transcriptase Activity of LINE-1 Enhanced by p53 Deficiency as a Vulnerability
2.3.3. Targeting YPA/TAZ Activity Enhanced by GOF mutp53 as a Vulnerability
3. Discussion
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug | Chemical Structure | Action on p53 | Trial Identifier | Cancer Type | Reference | Brief Summary/Current Status |
---|---|---|---|---|---|---|
APR-246 (eprenetapopt, PRIMA-1MET) | Mutp53 reactivation | NCT04383938 | Advanced solid tumor (bladder, gastric, NSCLC, urothelial) | [23] | Well tolerated for the combination with pembrolizumab | |
NCT03072043 | MDS/oligoblastic AML | [24] | Favorable outcomes with response rates for MDS (73%) and oligoblastic AML (64%) | |||
NCT03588078 | AML/MDS | [25] | Favorable outcomes with response rates for MDS (62%) and AML (33%) | |||
NCT03931291 | AML/MDS in post-HCT maintenance therapy | [26] | Improved RFS | |||
NCT03745716 | MDS | NA | NR, trial completed | |||
NCT02098343 | Platinum-sensitive recurrent HGSOC | NA | NR, trial completed | |||
NCT03268382 | Platinum-resistant recurrent HGSOC | NA | NR, trial completed | |||
NCT04214860 | Myeloid malignancies | NA | NR, trial completed | |||
PEITC (phenethyl isothiocyanate) | Mutp53 reactivation | NCT01790204 | Oral cancer | NA | NR, trial completed | |
ATO (arsenic trioxide/Trisenox) | Mutp53 reactivation | NCT03855371 | AML/MDS | NA | NR, recruiting patients | |
NCT04869475 | Refractory solid tumors | NA | NR, recruiting patients | |||
NCT04489706 | Recurrent and metastatic ovarian and endometrial cancer | NA | NR, recruiting patients | |||
NCT04695223 | Refractory solid tumors | NA | NR, recruiting patients | |||
HSP90 inhibitor (ganetespib/STA-9090) | Mutp53 degradation | NCT02012192 | High-grade platinum-resistant ovarian cancer | [27] | Confirm safe use of the combination | |
Atorvastatin | Mutp53 degradation | NCT04767984 | Longstanding ulcerative colitis | NA | NR, recruiting patients | |
NCT03560882 | Solid tumor and relapsed AML | NA | NR, recruiting patients | |||
ATO/Trisenox | Mutp53 degradation | NCT03381781 | AML | NA | NR, not recruiting yet | |
NCT03377725 | MDS | NA | NR, not recruiting yet | |||
Vorinostat/Zolinza/SAHA | Mutp53 degradation | NCT02042989 | Advanced malignancies | [28] | Limited effects | |
NCT01339871 | Advanced malignancies | [29] | Extended PFS | |||
Wee1 inhibitor (adavosertib/AZD1775/MK-1775) | Synthetic lethality to p53 | NCT01164995 | Refractory and resistant ovarian cancer | [30] | Enhance carboplatin efficacy | |
NCT01357161 | Platinum-sensitive ovarian tumors | [31] | Modest clinical benefit with improved PFS | |||
NCT02272790 | Platinum-resistant ovarian cancer | [32] | Some promising outcomes with carboplatin | |||
FOCUS4-C | Metastatic colorectal cancer with RAS | [33] | Improved PFS | |||
NCT03668340 | Recurrent uterine serous carcinoma | [34] | Significant activity (but p53 deficiency alone is not sufficient) | |||
NCT02688907 | Relapsed SCLC with CDKN2A | NA | NR, trial terminated | |||
NCT02593019 | Relapsed SCLC with CDKN2A | NA | NR, trial completed | |||
NCT02087241 | Untreated stage IV NSCLC | NA | NR, trial terminated | |||
NCT02087176 | NSCLC | NA | NR, trial terminated | |||
Lamivudine (3TC/Epivir/Zeffix/DELSTRIGO) | Inhibition of LINE-1 upregulated by p53 loss | NCT03144804 | Metastatic colorectal cancer | [35] | SD in 8 out of 32 cases | |
Zoledronic acid (ZA/Reclast/Zometa) and atorvastatin | ZA | Inhibition of YPA/TAZ activity enhanced by mutp53 | NCT03358017 | Triple negative breast cancer | NA | NR, recruiting patients |
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Nishikawa, S.; Iwakuma, T. Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials. Cancers 2023, 15, 429. https://doi.org/10.3390/cancers15020429
Nishikawa S, Iwakuma T. Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials. Cancers. 2023; 15(2):429. https://doi.org/10.3390/cancers15020429
Chicago/Turabian StyleNishikawa, Shigeto, and Tomoo Iwakuma. 2023. "Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials" Cancers 15, no. 2: 429. https://doi.org/10.3390/cancers15020429
APA StyleNishikawa, S., & Iwakuma, T. (2023). Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials. Cancers, 15(2), 429. https://doi.org/10.3390/cancers15020429