The p53/MDM2/MDMX-targeted therapies—a clinical synopsis

Jiang, Lingge; Zawacka-Pankau, Joanna

doi:10.1038/s41419-020-2445-9

Cited by 57 publications

(57 citation statements)

References 19 publications

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“…Detailed studies are needed to pin down which residues are responsible for the binding of PpIX to p53. Next, further studies showed that exo-PpIX is a dual inhibitor of MDM2-p53 and MDMX-p53 interactions as depicted in yeast-based reporter assay, fluorescence two-hybrid assay and immunoprecipitation [143]. PpIX induced apoptosis in leukemia cells without affecting healthy cells.…”

Section: Repurposed Drugs That Reactivate P53 and P73mentioning

confidence: 98%

“…p53 residues F19, W23 and L26 are responsible for binding with MDM2 and MDMX [27]. Taken the well-known structure of the MDM2-p53 complex, and the fact that the inhibition of the wild-type (wt) p53 via p53/MDM2/MDMX axis is essential for cancer to develop (reviewed in [4]), inhibition of the MDM2-and MDMX-p53 interactions has become a very promising strategy for cancer therapy and is described in more detail below. TAD domain of p53 is rendered unfolded and adapts transiently stable secondary structure.…”

Section: P53 Structurementioning

confidence: 99%

“…Studies demonstrated the feasibility of reactivating mutant p53 with small molecules reviewed in [42] and an advanced clinical example is described below. In cases in which TP53 gene remains intact, p53 protein is degraded by the upregulated or hyperactive MDM2 protein, which acts in concert with MDMX (reviewed in [4] and in [13]) (Figure 1). MDM2 was found overexpressed in many tumor types via several mechanism including gene amplification or enhanced transcription [43].…”

Section: P53 Inactivation In Cancermentioning

confidence: 99%

“…APR-246 also inhibits thioredoxin reductase and binds to gluthatione which boosts accumulation of reactive oxygen species and contributes to cancer cells' death (reviewed in [58]). The compound is studied in Phase III clinical trial in combination with Azacytidine in TP53 mutated Myledoysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) (reviewed in [4] and in [59]).…”

Section: Pharmacological Reactivation Of P53mentioning

confidence: 99%

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The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

Zawacka-Pankau

2020

Preprint

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p53 and p73 are critical tumor suppressors often inactivated in human cancers through various mechanisms. Owing to high structural homology, the proteins have many common functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 form a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni Syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of current standard of care and marginal benefit of newly approved therapies. Presently, the endeavours focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.

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Section: Repurposed Drugs That Reactivate P53 and P73mentioning

confidence: 98%

Section: P53 Structurementioning

confidence: 99%

Section: P53 Inactivation In Cancermentioning

confidence: 99%

Section: Pharmacological Reactivation Of P53mentioning

confidence: 99%

See 2 more Smart Citations

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

Zawacka-Pankau

2020

Preprint

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“…The REpurposing Drugs in Oncology database (ReDo) lists the drugs manifesting the anti-cancer potential and up to now includes 268 drugs (ReDO_DB) [4]. The list contains verteporfin (Visudyne  ), an analog of protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid showed to activate p53 and p73 [5].…”

Section: Introductionmentioning

confidence: 99%

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

Zawacka-Pankau¹

2020

Preprint

View full text Add to dashboard Cite

p53 and p73 are critical tumor suppressors inactivated in human cancers through various mechanisms. Owing to high structural homology, the proteins share many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and forms a critical barrier against cancer development and progression. It is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni Syndrome (LFS), the inherited cancer predisposition. Despite the ongoing effort, the treatment of cancers harbouring mutant p53 still remains challenging due to late diagnoses and the treatment-related toxicity and marginal benefit upon approval of new therapies. Presently, the efforts focus on activating p53 exclusively, neglecting the potential of the restoration of the p73 protein in tumors. Taken that several small molecules activating wild-type p53 have failed in clinical trials, and mutant p53 reactivating drugs have not been approved yet, there is a pressing need to develop new treatments activating p53 proteins. This review outlines the still despised therapeutic avenue, drug repurposing, which brings hope for the efficient reinstatement of the p53 protein family for improved cancer therapy.

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DFT calculations of electronic structure evaluation and intermolecular interactions of p53-derived peptides with cytotoxic effect on breast cancer

et al. 2021

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The p53/MDM2/MDMX-targeted therapies—a clinical synopsis

Cited by 57 publications

References 19 publications

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy - Drug Repurposing

DFT calculations of electronic structure evaluation and intermolecular interactions of p53-derived peptides with cytotoxic effect on breast cancer

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