• Special Issue Topic

    Proteolysis Targeting Chimera (PROTAC)

    Submission Deadline: July 31, 2021

    Guest Editor

    Dr. Matthias Baud E-Mail

    Lecturer in Medicinal Chemistry and Chemical Biology, University of Southampton, Southampton, UK

    Research Keywords: chemical biology; medicinal chemistry; small molecule; organic synthesis

    About the Special Issue

    Proteolysis targeting chimeras (PROTAC) are heterofunctional, bispecific molecules where two protein-binding probes are connected via a linker. The mechanism of action involves ternary complex formation in which one fragment interacts with the protein of interest (POI) and the other binds to a component of an ubiquitin ligase. This results in the poly-ubiquitination of the POI, which then undergoes proteasomal degradation, releasing the catalytic PROTAC. This strategy to reduce cellular protein levels has generated huge interest and excitement, and at present, there is significant research aimed at understanding the factors that determine functional efficiency. This is a truly exciting time for this field, which progressively shifted from a chemical biology concept to a new Eldorado for anticancer drug discovery. We feel that this special issue is particularly timely, and aims to provide an overview of the recent developments in the field of PROTAC, and applications to the development of novel candidate anticancer therapies.

    In this issue, we welcome Original Articles and Reviews spanning from the molecular sciences to advanced clinical work. Critical aspects include the development of novel molecular design principles and synthetic strategies for assembling PROTACs, structural biology and the thermodynamics of ternary complexes, the identification of novel anticancer targets, and the evaluation of new PROTACs in cancer cells and animal studies. In addition, structure activity relationship (SAR) studies and the correlation of molecular structures and properties with overall biological activity and selectivity profiles in cellular/animal studies will present a particular interest, as we believe that much is still to be done to derive useful design criteria for the rational design and optimization of PROTACs.

    Keywords: PROTAC; targeted anticancer therapy; induced protein degradation; ubiquitin-proteasome system; E3 ubiquitin ligase

    Published Articles

    Open Access
    Original Article
    The bromodomain and extra-terminal domain degrader MZ1 exhibits preclinical anti-tumoral activity in diffuse large B-cell lymphoma of the activated B cell-like type
    Aim: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targ [...] Read more.
    Chiara Tarantelli ... Francesco Bertoni
    Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:586–601
    DOI: https://doi.org/10.37349/etat.2021.00065
    Open Access
    The clinical advances of proteolysis targeting chimeras in oncology
    Proteolysis targeting chimeras (PROTACs) are a class of small molecules designed to target proteins for degradation. Their novel and unique modes of action provide PROTACs with the potential for the [...] Read more.
    Hao Xie ... Jason B. Fleming
    Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:511–521
    DOI: https://doi.org/10.37349/etat.2021.00061
    Open Access
    Proteolysis-targeting chimeras and their implications in breast cancer
    Breast cancer (BC) is a highly heterogeneous neoplasm of the mammary tissue, causing the deaths of a large number of women worldwide. Nearly 70% and 20% of BC cases are estro [...] Read more.
    Angeles C. Tecalco-Cruz ... Alberto Rojas-Ochoa
    Published: December 31, 2021 Explor Target Antitumor Ther. 2021;2:496–510
    DOI: https://doi.org/10.37349/etat.2021.00060
    Open Access
    Novel approaches for the rational design of PROTAC linkers
    Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together b [...] Read more.
    Almaz Zagidullin ... Emil Bulatov
    Published: October 30, 2020 Explor Target Antitumor Ther. 2020;1:381–390
    DOI: https://doi.org/10.37349/etat.2020.00023
    Open Access
    Current strategies for the design of PROTAC linkers: a critical review
    PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead”  [...] Read more.
    Robert I. Troup ... Matthias G. J. Baud
    Published: October 30, 2020 Explor Target Antitumor Ther. 2020;1:273–312
    DOI: https://doi.org/10.37349/etat.2020.00018
    Open Access
    PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors
    BCL-XL is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-XL has also been identified [...] Read more.
    Peiyi Zhang ... Guangrong Zheng
    Published: August 31, 2020 Explor Target Antitumor Ther. 2020;1:259–272
    DOI: https://doi.org/10.37349/etat.2020.00017
    Open Access
    Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors
    Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell  [...] Read more.
    Rachael Arthur ... Graham Packham
    Published: June 29, 2020 Explor Target Antitumor Ther. 2020;1:131–152
    DOI: https://doi.org/10.37349/etat.2020.00009