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Pharmaceuticals
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Targeting p53 by Small Molecules: Application in Oncology
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Targeting p53 by Small Molecules: Application in Oncology

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 11428

Special Issue Editors

Dr. Maria M. M. Santos

E-Mail Website
Guest Editor
Faculty of Pharmacy, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal
Interests: organic synthesis; medicinal chemistry; heterocycles; anticancer drugs; p53 activators; NMDA receptor antagonists
Prof. Dr. Lucília Saraiva

E-Mail Website
Co-Guest Editor
LAQV/REQUIMTE, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 228, 4050-313 Porto, Portugal
Interests: cancer pharmacology; targeted therapy; drug discovery; p53 family proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The tumor suppressor protein p53, often referred as the “guardian of the genome”, is among the most privileged targets in anticancer therapy due to its key role in virtually all cancer hallmarks. In most human tumors, the p53 tumor suppressor function is inactivated, through either mutation in the TP53 gene or via negative regulators (e.g., MDM2 and MDMX). Several small-molecule activators of wild-type p53 function have been developed through the inhibition of MDM2, and some have reached clinical trials. However, there is still a limited number of small molecules that can reactivate mutant p53 function, as well as dual inhibitors of MDM2 and MDMX. In this Special Issue on “Targeting p53 with small molecules: application in oncology”, we aim to cover original reviews and research articles focused on new small-molecule p53 activators for anticancer therapy and address the distinct strategies for restoring protein function.

Dr. Maria M. M. Santos
Prof. Dr. Lucília Saraiva
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • activator 
  • cancer 
  • inhibitor 
  • wild-type p53 
  • MDM2 
  • MDMX 
  • mutant p53 
  • small molecules 
  • transcription factor 
  • tumor suppressor.

Published Papers (4 papers)

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Research

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26 pages, 3580 KiB  
Article
Metabolism-Guided Optimization of Tryptophanol-Derived Isoindolinone p53 Activators
by Valentina Barcherini, Joana B. Loureiro, Ana Sena, Catarina Madeira, Paula Leandro, Lucília Saraiva, Alexandra M. M. Antunes and Maria M. M. Santos
Pharmaceuticals 2023, 16(2), 146; https://doi.org/10.3390/ph16020146 - 19 Jan 2023
Cited by 3 | Viewed by 1884
Abstract
For the first time, the pharmacokinetic (PK) profile of tryptophanol-derived isoindolinones, previously reported as p53 activators, was investigated. From the metabolites’ identification, performed by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-HRMS/MS), followed by their preparation and structural elucidation, it was [...] Read more.
For the first time, the pharmacokinetic (PK) profile of tryptophanol-derived isoindolinones, previously reported as p53 activators, was investigated. From the metabolites’ identification, performed by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-HRMS/MS), followed by their preparation and structural elucidation, it was possible to identify that the indole C2 and C3 are the main target of the cytochrome P450 (CYP)-promoted oxidative metabolism in the tryptophanol-derived isoindolinone scaffold. Based on these findings, to search for novel p53 activators a series of 16 enantiopure tryptophanol-derived isoindolinones substituted with a bromine in indole C2 was prepared, in yields of 62–89%, and their antiproliferative activity evaluated in human colon adenocarcinoma HCT116 cell lines with and without p53. Structural optimization led to the identification of two (S)-tryptophanol-derived isoindolinones 3.9-fold and 1.9-fold more active than hit SLMP53-1, respectively. Compounds’ metabolic stability evaluation revealed that this substitution led to a metabolic switch, with the impact of Phase I oxidative metabolism being minimized. Through differential scanning fluorimetry (DSF) experiments, the most active compound of the series in cell assays led to an increase in the protein melting temperature (Tm) of 10.39 °C, suggesting an effective binding to wild-type p53 core domain. Full article
(This article belongs to the Special Issue Targeting p53 by Small Molecules: Application in Oncology)
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12 pages, 1927 KiB  
Article
HMG-CoA Reductase Inhibitor Statins Activate the Transcriptional Activity of p53 by Regulating the Expression of TAZ
by Chiharu Miyajima, Yurika Hayakawa, Yasumichi Inoue, Mai Nagasaka and Hidetoshi Hayashi
Pharmaceuticals 2022, 15(8), 1015; https://doi.org/10.3390/ph15081015 - 17 Aug 2022
Cited by 9 | Viewed by 1881
Abstract
Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated [...] Read more.
Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated that TAZ inhibited the tumor suppressor functions of p53 and enhanced cell proliferation. Statins, which are used to treat dyslipidemia, have been reported to suppress the activity of TAZ and exert anti-tumor effects. In the present study, we focused on the regulation of p53 functions by TAZ and investigated whether statins modulate these functions via TAZ. The results obtained suggest that statins, such as simvastatin and fluvastatin, activated the transcriptional function of p53 by suppressing TAZ protein expression. Furthermore, co-treatment with simvastatin and anti-tumor agents that cooperatively activate p53 suppressed cancer cell survival. These results indicate a useful mechanism by which statins enhance the effects of anti-tumor agents through the activation of p53 and may represent a novel approach to cancer therapy. Full article
(This article belongs to the Special Issue Targeting p53 by Small Molecules: Application in Oncology)
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15 pages, 2837 KiB  
Article
Application of In Silico Filtering and Isothermal Titration Calorimetry for the Discovery of Small Molecule Inhibitors of MDM2
by Hen Alali, Itai Bloch, Irena Rapaport, Luisa Rodrigues, Inbal Sher, Tamar Ansbacher and Maayan Gal
Pharmaceuticals 2022, 15(6), 752; https://doi.org/10.3390/ph15060752 - 16 Jun 2022
Viewed by 2399
Abstract
The initial discovery phase of protein modulators, which consists of filtering molecular libraries and in vitro direct binding validation, is central in drug discovery. Thus, virtual screening of large molecular libraries, together with the evaluation of binding affinity by isothermal calorimetry, generates an [...] Read more.
The initial discovery phase of protein modulators, which consists of filtering molecular libraries and in vitro direct binding validation, is central in drug discovery. Thus, virtual screening of large molecular libraries, together with the evaluation of binding affinity by isothermal calorimetry, generates an efficient experimental setup. Herein, we applied virtual screening for discovering small molecule inhibitors of MDM2, a major negative regulator of the tumor suppressor p53, and thus a promising therapeutic target. A library of 20 million small molecules was screened against an averaged model derived from multiple structural conformations of MDM2 based on published structures. Selected molecules originating from the computational filtering were tested in vitro for their direct binding to MDM2 via isothermal titration calorimetry. Three new molecules, representing distinct chemical scaffolds, showed binding to MDM2. These were further evaluated by exploring structure-similar chemical analogues. Two scaffolds were further evaluated by de novo synthesis of molecules derived from the initial molecules that bound MDM2, one with a central oxoazetidine acetamide and one with benzene sulfonamide. Several molecules derived from these scaffolds increased wild-type p53 activity in MCF7 cancer cells. These set a basis for further chemical optimization and the development of new chemical entities as anticancer drugs. Full article
(This article belongs to the Special Issue Targeting p53 by Small Molecules: Application in Oncology)
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Review

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39 pages, 17463 KiB  
Review
Therapeutic Strategies to Activate p53
by Angelo Aguilar and Shaomeng Wang
Pharmaceuticals 2023, 16(1), 24; https://doi.org/10.3390/ph16010024 - 24 Dec 2022
Cited by 10 | Viewed by 4272
Abstract
The p53 protein has appropriately been named the “guardian of the genome”. In almost all human cancers, the powerful tumor suppressor function of p53 is compromised by a variety of mechanisms, including mutations with either loss of function or gain of function and [...] Read more.
The p53 protein has appropriately been named the “guardian of the genome”. In almost all human cancers, the powerful tumor suppressor function of p53 is compromised by a variety of mechanisms, including mutations with either loss of function or gain of function and inhibition by its negative regulators MDM2 and/or MDMX. We review herein the progress made on different therapeutic strategies for targeting p53. Full article
(This article belongs to the Special Issue Targeting p53 by Small Molecules: Application in Oncology)
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