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Pharmaceutics
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State of Art in Protein Degraders and Autophagy Modulators in...
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State of Art in Protein Degraders and Autophagy Modulators in the Cancer Treatment

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 December 2022) | Viewed by 11818

Special Issue Editors

Prof. Dr. Giovanni Piccoli

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Guest Editor
Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy
Interests: protein aggregation; neurobiology; Parkinson’s disease; autophagy
Special Issues, Collections and Topics in MDPI journals
Dr. María Dolores Pérez-Carrión

E-Mail Website
Guest Editor
Unidad Asociada Neurodeath, Universidad de Castilla-La Mancha, 02006 Albacete, Spain
Interests: autophagy; pharmacology; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Fabrizia Guarnieri

E-Mail Website
Guest Editor
1. Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
2. School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy
Interests: neurobiology; autophagy; biochemistry

Special Issue Information

Dear Colleagues, 

Almost all cellular functions depend on the steady state of the proteome, achieved through a balance between protein synthesis and degradation. Dysregulation in protein homeostasis is emerging as a causative event in a number of diseases, including cancer. The imbalance in protein homeostasis may overload the cellular protein handling machinery and, eventually, brings proteotoxic stress. The proteotoxic stress is harmful: eukaryotic cells can rely on multiple protein quality control pathways for resolving the proteotoxic stress, including autophagy. Numerous tumor suppressor oncogenes interfere with autophagy, including the oncosuppressor p53. The role of autophagy in cancer is now emerging: autophagy deregulation is among the key features for tumor progression. Indeed, the dysregulation of protein levels, such as the overexpression of oncoproteins can trigger the neoplastic process. The selective degradation of target proteins is an attractive approach to tackle cancer progression.  Following a long and also tragic history, thalidomide was discovered to drive proteins towards proteasomal degradation upon coupling to an E3 ubiquitin ligase. This discovery lead to the development of chemical platforms allowing the targeted degradation of previously undruggable proteins.

This Special Issue invites international researchers in the area of new strategies to induce targeted protein degradation and modulate autophagy in therapeutic, authentic models. We welcome original research articles and reviews focused on the identification of natural and synthetic pharmacological leads from HTS campaigns, on the rational design and structure–activity relationships of small molecules, alternative systems to deliver pro-drugs, and preclinical evaluation of promising leads.

I look forward to receiving your contributions.

Prof. Dr. Giovanni Piccoli
Dr. María Dolores Pérez-Carrión
Dr. Fabrizia Claudia Guarnieri
Guest Editors

Manuscript Submission Information

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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. Pharmaceutics 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

  • autophagy
  • degrader therapeutic
  • prodrugs
  • in vitro models
  • in vivo models
  • pharmacokinetics
  • thalidomide
  • Proteolysis Targeting Chimeric Molecules
  • delivery systems
  • rational drug design

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Published Papers (4 papers)

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Research

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16 pages, 6648 KiB  
Article
Negr1-Derived Peptides Trigger ALK Degradation and Halt Neuroblastoma Progression In Vitro and In Vivo
by Francesca Pischedda, Alessia Ghirelli, Vasvi Tripathi and Giovanni Piccoli
Pharmaceutics 2023, 15(9), 2307; https://doi.org/10.3390/pharmaceutics15092307 - 12 Sep 2023
Cited by 3 | Viewed by 1297
Abstract
Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the [...] Read more.
Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the somatically acquired alterations. ALK kinase activity is currently one of the main targets for pharmacological strategies. However, evidence from ALK fusion-positive lung cancer studies has shown that resistance to ALK inhibition arises during the therapy, causing a relapse within several years. IgLONs are membrane-bound proteins involved in cell-to-cell adhesion. The expression of the IgLON family results altered in different cancers. We found that the IgLON member Negr1 is downregulated in neuroblastoma. The ectopic overexpression of Negr1 impairs neuroblastoma growth in vitro and in vivo. Negr1 exists as a GPI-anchored membrane-bound protein and as a soluble protein released upon metalloprotease cleavage. We generated and characterized a panel of Negr1-derived peptides. The treatment with Negr1 protein and derived peptides induce ALK downregulation and halt neuroblastoma progression in vitro and in vivo. Full article
(This article belongs to the Special Issue State of Art in Protein Degraders and Autophagy Modulators in the Cancer Treatment)
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15 pages, 2994 KiB  
Article
Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation
by Martina Pedrini, Angelo Iannielli, Lorenzo Meneghelli, Daniele Passarella, Vania Broccoli and Pierfausto Seneci
Pharmaceutics 2023, 15(5), 1467; https://doi.org/10.3390/pharmaceutics15051467 - 11 May 2023
Cited by 5 | Viewed by 3129
Abstract
The search for disease-modifying agents targeted against Parkinson’s disease led us to rationally design a small array of six Anle138b-centered PROTACs, 7a,b, 8a,b and 9a,b, targeting αSynuclein (αSyn) aggregates for binding, polyubiquitination by the E3 [...] Read more.
The search for disease-modifying agents targeted against Parkinson’s disease led us to rationally design a small array of six Anle138b-centered PROTACs, 7a,b, 8a,b and 9a,b, targeting αSynuclein (αSyn) aggregates for binding, polyubiquitination by the E3 ligase Cereblon (CRBN), and proteasomal degradation. Lenalidomide and thalidomide were used as CRBN ligands and coupled with amino- and azido Anle138b derivatives through flexible linkers and coupling reactions (amidation, ‘click’ chemistry). Four Anle138b-PROTACs, 8a,b and 9a,b, were characterized against in vitro αSyn aggregation, monitoring them in a Thioflavin T (ThT) fluorescence assay and in dopaminergic neurons derived from a set of isogenic pluripotent stem cell (iPSC) lines with SNCA multiplications. Native and seeded αSyn aggregation was determined with a new biosensor, and a partial correlation between αSyn aggregation, cellular dysfunctions, and neuronal survival was obtained. Anle138b-PROTAC 8a was characterized as the most promising αSyn aggregation inhibitor/degradation inducer, with potential usefulness against synucleinopathies and cancer. Full article
(This article belongs to the Special Issue State of Art in Protein Degraders and Autophagy Modulators in the Cancer Treatment)
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Review

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18 pages, 1641 KiB  
Review
Current Status of Oligonucleotide-Based Protein Degraders
by Po-Chang Shih, Miyako Naganuma, Yosuke Demizu and Mikihiko Naito
Pharmaceutics 2023, 15(3), 765; https://doi.org/10.3390/pharmaceutics15030765 - 24 Feb 2023
Cited by 6 | Viewed by 2889
Abstract
Transcription factors (TFs) and RNA-binding proteins (RBPs) have long been considered undruggable, mainly because they lack ligand-binding sites and are equipped with flat and narrow protein surfaces. Protein-specific oligonucleotides have been harnessed to target these proteins with some satisfactory preclinical results. The emerging [...] Read more.
Transcription factors (TFs) and RNA-binding proteins (RBPs) have long been considered undruggable, mainly because they lack ligand-binding sites and are equipped with flat and narrow protein surfaces. Protein-specific oligonucleotides have been harnessed to target these proteins with some satisfactory preclinical results. The emerging proteolysis-targeting chimera (PROTAC) technology is no exception, utilizing protein-specific oligonucleotides as warheads to target TFs and RBPs. In addition, proteolysis by proteases is another type of protein degradation. In this review article, we discuss the current status of oligonucleotide-based protein degraders that are dependent either on the ubiquitin–proteasome system or a protease, providing a reference for the future development of degraders. Full article
(This article belongs to the Special Issue State of Art in Protein Degraders and Autophagy Modulators in the Cancer Treatment)
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43 pages, 9258 KiB  
Review
Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs
by Arvind Negi, Kavindra Kumar Kesari and Anne Sophie Voisin-Chiret
Pharmaceutics 2022, 14(11), 2523; https://doi.org/10.3390/pharmaceutics14112523 - 19 Nov 2022
Cited by 9 | Viewed by 4039
Abstract
Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such [...] Read more.
Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such approaches have intrinsic flaws, such as pico-to-nanomolar range binding affinity and continuous dosage after a time interval for sustained inhibition of POI. These shortcomings were addressed by event-driven pharmacology-based approaches, which degrade the POI rather than inhibit it. One such example is PROTACs (Proteolysis targeting chimeras), which has become one of the highly successful strategies of event-driven pharmacology (pharmacology that does the degradation of POI and diminishes its functions). The selective targeting of estrogen receptor subtypes is always challenging for chemical biologists and medicinal chemists. Specifically, estrogen receptor α (ER-α) is expressed in nearly 70% of breast cancer and commonly overexpressed in ovarian, prostate, colon, and endometrial cancer. Therefore, conventional hormonal therapies are most prescribed to patients with ER + cancers. However, on prolonged use, resistance commonly developed against these therapies, which led to selective estrogen receptor degrader (SERD) becoming the first-line drug for metastatic ER + breast cancer. The SERD success shows that removing cellular ER-α is a promising approach to overcoming endocrine resistance. Depending on the mechanism of degradation of ER-α, various types of strategies of developed. Full article
(This article belongs to the Special Issue State of Art in Protein Degraders and Autophagy Modulators in the Cancer Treatment)
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