Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer
Abstract
:1. Introduction
2. p53 Structure and Mutations Exploited for Drug Development
2.1. p53 Structure Exploited for Drugs Reactivating p53 Signaling
2.2. Conformational Changes of p53 Mutants Utilized for Drugs That Restore Wild-Type Function
2.3. p53 Transgenic Mouse Models (p53 Knockout, Mutant p53 Knock-Ins, and Inducible Models) Provide a Powerful Tool to Investigate p53 Function
3. Strategies for Boosting Wild-Type p53 Activity in Cancer: Gene Therapy, Cytotoxic Chemotherapy, MDM2/MDMX(MDM4) Inhibitors, p53-Binding Compounds, Targeting p53 PTMs
3.1. Small Molecules Can Directly Target Wild-Type p53 Protein
3.2. Small Molecules Can Activate p53 via Targeting MDM2/MDMX(MDM4)
3.3. Small Molecules Can Induce p53 Transcription via Post-Translational Modifications
4. p53-Dependent and p53-Independent Strategies for Targeting p53 Pathway Restoration in p53-Mutated Cancers
4.1. Restoration of Wild-Type Function in Tumors Expressing Mutant p53
4.2. Therapeutic Induction of Mutant p53 Degradation
4.3. Activation of p73 to Bypassing Mutant p53 in Restoration of Wild-Type p53 Function
4.4. Restoration of p53 Pathway Signaling Independent of p53 through Non-Canonical Regulatory Pathways
5. Targeting p53 Function in Immunotherapy: Bispecific Antibodies, Gene Therapy, Small Molecule Combinations
5.1. Activation of Wild-Type p53 for Immunotherapy Using Immune Checkpoint Inhibitors
5.2. Targeting Mutant p53 in Immunotherapy
6. Combination Therapies Targeting p53 Cell Cycle Checkpoints, MDM2-p53 Inhibition, or Mutant p53
6.1. Targeting p53 in Combination with Cell Stress Signaling
6.2. Targeting p53 in Combination with Inhibition of Raf/MEK/ERK Pathways
6.3. Targeting p53 (Wild-Type and Mutant) in Combination with Conventional Chemotherapy
6.4. Combination Targeting p53 Cell Cycle Checkpoints in p53 Mutated Cancer Cells
7. Summary and Prospects
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compound/Peptide/Antibody | Chemical Name and/or Class | Target/Mechanism | Clinical Development | References | ||
---|---|---|---|---|---|---|
Targeting wild p53 activation | p53 activator | RITA | Binds to p53 and prevents WT p53 degradation by blocking interaction with MDM2 | Experimental and/or preclinical | [78] | |
MDM2 inhbitors | Nutlin-3a | Cis-imidazoline | Blocks the interactive binding sites of p53 and MDM2, dramatically increasing the half-life of p53 and activating p53-mediated transcription. | The listed inhibitors, except nutlin-3a, have undergone or are currently undergoing clinical trials | [9,79] | |
RG7112 | Cis-imidazoline | |||||
RG7388 | Cis-imidazoline | |||||
RG7775 | Pegylated prodrug idasanutlin | |||||
MI-77301 | Spirooxindole | |||||
AMG232 | Piperidinone | |||||
SAR405838 | Piperidinone | |||||
MK-8242 | 2(1H)-Pyrimidinone | |||||
CGM097 | Dihydroisoquinolinone | |||||
DS-3032b | Unknown | |||||
HDM201 | Imidazopyrrolidinone | |||||
MDM2/MDMX(MDM4) dual inhibitors | ALRN-6924 | Stapled peptide | Blocks the interactive binding sites of p53 and MDM2/MDMX(MDM4), dramatically increasing the half-life of p53 and activating p53-mediated transcription. | currently undergoing clinical trials | ||
RO-5963 RO-2443 | indolyl hydantoin | Binds to MDMX(MDM4)/MDM2 and blocks p53-MDM2/MDMX interaction | [32] | |||
MDM2 degradators | PROTAC 8, A1874 | IMiD-based MDM2 | Targeted degradation of MDM2 using proteolysis targeting chimeras (PROTACs) | Experimental and/or preclinical | [9,80] | |
Gene therapy- based on oncolytic Viruses | ONYX-015 | Recombinant adenovirus with wild-type p53 (Ad-p53) | A mutant adenovirus with a deleted E1B-55Kd gene commonly fails to replicate efficiently in cells with a wild-type p53 but replicates in many (but not all) cells with a mutant p53 gene. | In clinical trials | [9,81,82] | |
Gendicine (Ad-53) | Recombinant adenovirus engineered to express wildtype-p53 (rAd-p53) | Gene replacement (gene therapy) | Approved in 2003 by the China Food and Drug Administration (CFDA) to treat head and neck cancer | [9,83,84] | ||
Targeting mutant p53 | Restoration of wild-type function to mutant p53 | CP-31398 | Styrylquinazoline | Cysteine-binding compounds, Michael acceptor binding to mutant p53 | Experimental and/or preclinical | [85] |
PRIMA-1 | Quinuclidinone | Cysteine-binding compound is converted to MQ, which binds mutant p53 by Michael addition | Experimental and/or preclinical | [86] | ||
APR-246 | Quinuclidinone | Cysteine-binding compound is converted to MQ, which binds mutant p53 by Michael addition | Phase Ib/II for ovarian cancer, MDS, and oesophageal cancer | [87] | ||
MIRA-1 | Maleimide | Michael acceptor binding to mutant p53 | Experimental and/or preclinical | [88] | ||
STIMA-1 | Styrylquinazoline | Michael acceptor binding to mutant p53 | Experimental and/or preclinical | [89] | ||
3-Benzoylacrylic acid | Benzoylacrylate | Binds to mutant p53 by Michael addition | Experimental and/or preclinical | [90] | ||
KSS-9 | Piperlongumine | Microtubule poison; redox; Michael acceptor binding to mutant p53 | Experimental and/or preclinical | [91] | ||
PK11007 | Sulfonylpyrimidine | Binds to mutant p53 by nucleophilic aromatic substitution | Experimental and/or preclinical | [92] | ||
ZMC1 ZMC2 ZMC3 ZN-1 | Thiosemicarbazone | Zn2+ chelator | Experimental and/or preclinical | [48] | ||
COTI-2 | Thiosemicarbazone | Zn2+ chelator | Phase I for gynecological tumors and head and neck cancer | [93] | ||
SLM P53-1 | Tryptophanol-derived oxazoloisoindolinone | restores wt-like DNA binding ability to mut p53R280K Bridges extra interaction between p53 and DNA that rescues DNA binding and transcription activity | Experimental and/or preclinical | [94,95] | ||
SLM p53-2 | Tryptopha-nol-derived oxa-zoloisoindolinone | Restores wild-type-like conformation and DNA-binding ability, possibly by enhancing interaction with Hsp70. | Experimental and/or preclinical | [96] | ||
MB725 MB710 | Aminobenzothiazole | Binds to Y220C of p53 DBD | Experimental and/or preclinical | [46] | ||
PK083 Pk9318 | Carbazole | Binds to Y220C of p53 DBD | [44,45] | |||
pCAPs | Peptides | Binds to mutant p53 and promotes refolding | Experimental and/or preclinical | [97] | ||
Mutant p53 degradation | Ganetespib Onalespib Luminespib TAS-116 | Depletion of mutant p53 using HSP90 inhibitors or statins | In clinical trials | [9,98] | ||
Vorinostat | Suberanilohydroxamic acid (SAHA) | Histone deacetylase (HDAC) inhibitor, destabilizes mut p53 through inhibition of the HDAC6-HSP90 chaperone axis, and at the same time, inhibit the transcription of mutant p53 through HDAC8 | In clinical trials | [72,77,99,100] | ||
Atorvastatin Lovastatin | Statin drugs, Inhibition of mevalonate pathway | In clinical trials | [9,101] | |||
NSC59984 | Activation of MDM2 | [21] | ||||
Spaurtin | Chaperone-mediated autophagy (CMA) pathway | [102] | ||||
Reacp53 | Peptide | Disrupts mutant-p53 aggregates | Experimental and/or preclinical | [8] | ||
Interruption of mutant GOF | RETRA | 2-(4,5-Dihydro-1,3-thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl) ethanone | Binds to mutant p53 and disrupts mutant-p53–p73 complexes | Experimental and/or preclinical | [103] | |
Prodigiosin | Disrupts mutant-p53–p73 complexes | Experimental and/or preclinical | [22] | |||
Immunotherapy | H2-scDb H2-Fab | Bispecific antibody | Bispecific antibody links T cells to cancer cells with one arm binding to T cell receptor and the other arm binding to HLA-mutant p53 R175H peptide on cancer cell surface. | Experimental and/or preclinical | [104] |
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Zhang, S.; Carlsen, L.; Hernandez Borrero, L.; Seyhan, A.A.; Tian, X.; El-Deiry, W.S. Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules 2022, 12, 548. https://doi.org/10.3390/biom12040548
Zhang S, Carlsen L, Hernandez Borrero L, Seyhan AA, Tian X, El-Deiry WS. Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer. Biomolecules. 2022; 12(4):548. https://doi.org/10.3390/biom12040548
Chicago/Turabian StyleZhang, Shengliang, Lindsey Carlsen, Liz Hernandez Borrero, Attila A. Seyhan, Xiaobing Tian, and Wafik S. El-Deiry. 2022. "Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer" Biomolecules 12, no. 4: 548. https://doi.org/10.3390/biom12040548