Submit to Molecules Review for Molecules Propose a Special Issue

Journal Browser

► Journal Browser

Past, Present and Future of Novel Therapeutic Modalities in Development for Targeted Protein Degradation

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 20712

Share This Special Issue

Special Issue Editors

Dr. Li Chai

E-Mail Website
Guest Editor

Brigham Women’s Hospital, Boston, MA, USA
Interests: transcription factors; HDACi; SALL4; PROTAC; drug discovery & development
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Daniel G. Tenen

E-Mail Website
Guest Editor

1. Director, Cancer Science Institute of Singapore & Head, Blood Program, Harvard Stem Cell Institute, Cambridge, MA, USA
2. Distinguished Professor, Department of Medicine, National University of Singapore; and Director, Cancer Science Institute of Singapore, Singapore
Interests: hematopoiesis; transcription factors; SALL4; C/EBPa; PROTAC; RNA biology; drug development
Special Issues, Collections and Topics in MDPI journals

Dr. Susumu Kobayashi

E-Mail Website
Guest Editor

1. Chief, Division of Translational Genomics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Japan, Tokyo, Japan
2. Associate Professor, Harvard Medical School, Boston, MA, USA
Interests: transcription factors; C/EBPa; EGFR tyrosine kinase inhibitors; drug discovery and development
Special Issues, Collections and Topics in MDPI journals

Dr. Sridhar Radhakrishnan

E-Mail Website
Guest Editor

Research Fellow, Cancer Science Institute of Singapore, Singapore
Interests: small molecule; fragments; PROTAC; structure/ligand based; drug development; nanoparticles/fibers/materials; drug delivery; formulations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ubiquitination-mediated targeted protein degradation is a natural phenomenon involving the proteasome which tends to degrade or break the peptidic bonds of an unwanted or an excess protein. Novel therapeutic modalities have evolved with promise leveraging this innate cellular mechanism and several advances were reported by drug discovery researchers and drug developers. Proximity-inducing techniques have been evolving to enable protein degradation and small molecular glues, heterobifunctional degraders, PROTACs, PICs, TRACTACs, RiboTACs, AutoTACs, and AbTACs were being developed. Attempts to degrade transcription factors were proven successful and promising. Out of the box and beyond the rule of five degrader drugs were developed with greater target engagement, cellular permeability and oral bioavailability. Further AI and Machine learning tools have fuelled the degrader drug development envisioning structural aspects of degraders, targeted protein and the proximity induced complexes. Many pharma companies and start-up biotechs are involved in the development of a wide spectrum of degraders because of their huge potential. The past, current status and prospective future of these protein degrader drugs will be the main objective of this Special Issue.

In this Special Issue, we invite researchers to submit their latest research findings on different degradation aspects, targets, and E3 ligases or review articles related to these degraders for the treatment of cancer and other diseases. Different classes of ligands for target protein binding and E3 ligase binding, and chain length of the linkers will be helpful for readers/researchers involved in drug development, and hence, we encourage submissions discussing these aspects as well. Apart from conventional molecular glues or bifunctional target protein degraders, we invite articles based on large molecule-based degraders, and other less common unconventional degraders.

Dr. Li Chai
Prof. Dr. Daniel G. Tenen
Dr. Susumu Kobayashi
Dr. Sridhar Radhakrishnan
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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

proteolysis targeting chimera (PROTAC)
targeted protein degradation
dual motif drug molecules
CRBN binders, linkers/conjugates
antibody drug conjugates
RNA therapeutics

Published Papers (5 papers)

Download All Papers

Research

Jump to: Review

17 pages, 3166 KiB

Open AccessArticle

A First-Class Degrader Candidate Targeting Both KRAS G12D and G12V Mediated by CANDDY Technology Independent of Ubiquitination

by Etsuko Miyamoto-Sato, Satoshi Imanishi, Lijuan Huang, Shoko Itakura, Yoichi Iwasaki and Masamichi Ishizaka

Molecules 2023, 28(14), 5600; https://doi.org/10.3390/molecules28145600 - 24 Jul 2023

Cited by 3 | Viewed by 3444

Abstract

“Undruggable” targets such as KRAS are particularly challenging in the development of drugs. We devised a novel chemical knockdown strategy, CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics) technology, which promotes protein degradation using small molecules (CANDDY molecules) that are conjugated to a degradation tag (CANDDY tag) modified from proteasome inhibitors. We demonstrated that CANDDY tags allowed for direct proteasomal target degradation independent of ubiquitination. We synthesized a KRAS-degrading CANDDY molecule, TUS-007, which induced degradation in KRAS mutants (G12D and G12V) and wild-type KRAS. We confirmed the tumor suppression effect of TUS-007 in subcutaneous xenograft models of human colon cells (KRAS G12V) with intraperitoneal administrations and in orthotopic xenograft models of human pancreatic cells (KRAS G12D) with oral administrations. Thus, CANDDY technology has the potential to therapeutically target previously undruggable proteins, providing a simpler and more practical drug targeting approach and avoiding the difficulties in matchmaking between the E3 enzyme and the target. Full article

(This article belongs to the Special Issue Past, Present and Future of Novel Therapeutic Modalities in Development for Targeted Protein Degradation)

► Show Figures

Graphical abstract

Review

Jump to: Research

27 pages, 6555 KiB

Open AccessReview

PROTACs in the Management of Prostate Cancer

by Poornachandra Yedla, Ahmed O. Babalghith, Vindhya Vasini Andra and Riyaz Syed

Molecules 2023, 28(9), 3698; https://doi.org/10.3390/molecules28093698 - 25 Apr 2023

Cited by 5 | Viewed by 3252

Abstract

Cancer treatments with targeted therapy have gained immense interest due to their low levels of toxicity and high selectivity. Proteolysis-Targeting Chimeras (PROTACs) have drawn special attention in the development of cancer therapeutics owing to their unique mechanism of action, their ability to target undruggable proteins, and their focused target engagement. PROTACs selectively degrade the target protein through the ubiquitin–proteasome system, which describes a different mode of action compared to conventional small-molecule inhibitors or even antibodies. Among different cancer types, prostate cancer (PC) is the most prevalent non-cutaneous cancer in men. Genetic alterations and the overexpression of several genes, such as FOXA1, AR, PTEN, RB1, TP53, etc., suppress the immune response, resulting in drug resistance to conventional drugs in prostate cancer. Since the progression of ARV-110 (PROTAC for PC) into clinical phases, the focus of research has quickly shifted to protein degraders targeting prostate cancer. The present review highlights an overview of PROTACs in prostate cancer and their superiority over conventional inhibitors. We also delve into the underlying pathophysiology of the disease and explain the structural design and linkerology strategies for PROTAC molecules. Additionally, we touch on the various targets for PROTAC in prostate cancer, including the androgen receptor (AR) and other critical oncoproteins, and discuss the future prospects and challenges in this field. Full article

(This article belongs to the Special Issue Past, Present and Future of Novel Therapeutic Modalities in Development for Targeted Protein Degradation)

► Show Figures

Figure 1

21 pages, 9555 KiB

Open AccessReview

PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities

by Xuelian Liu, Anjin Wang, Yuying Shi, Mengyuan Dai, Miao Liu and Hong-Bing Cai

Molecules 2023, 28(3), 1217; https://doi.org/10.3390/molecules28031217 - 26 Jan 2023

Cited by 6 | Viewed by 3806

Abstract

The epigenetic regulation of gene functions has been proven to be strongly associated with the development and progression of cancer. Reprogramming the cancer epigenome landscape is one of the most promising target therapies in both treatments and in reversing drug resistance. Proteolytic targeted chimeras (PROTACs) are an emerging therapeutic modality for selective degradation via the native ubiquitin-proteasome system. Rapid advances in PROTACs have facilitated the exploration of targeting epigenetic proteins, a lot of PROTAC degraders have already been designed in the field of epigenetic cancer therapy, and PROTACs targeting epigenetic proteins can better exploit target druggability and improve the mechanistic understanding of the epigenetic regulation of cancer. Thus, this review focuses on the progress made in the development of PROTAC degraders and PROTAC drugs targeting epigenetics in cancer and discusses challenges and future opportunities for the field. Full article

(This article belongs to the Special Issue Past, Present and Future of Novel Therapeutic Modalities in Development for Targeted Protein Degradation)

► Show Figures

Figure 1

14 pages, 902 KiB

Open AccessReview

Proteolysis-Targeting Chimeras (PROTACs) in Cancer Therapy: Present and Future

by Rui Li, Miao Liu, Zhenya Yang, Jiao Li, Yuxin Gao and Ruirong Tan

Molecules 2022, 27(24), 8828; https://doi.org/10.3390/molecules27248828 - 12 Dec 2022

Cited by 10 | Viewed by 3305

Abstract

The PROteolysis TArgeting Chimeras (PROTACs) is an innovative technique for the selective degradation of target proteins via the ubiquitin–proteasome system. Compared with traditional protein inhibitor drugs, PROTACs exhibit advantages in the efficacy and selectivity of and in overcoming drug resistance in cancer therapy, providing new insights into the discovery of anti-cancer drugs. In the last two decades, many PROTAC molecules have been developed to induce the degradation of cancer-related targets, and they have been subjected to clinical trials. Here, we comprehensively review the historical milestones and latest updates in PROTAC technology. We focus on the structures and mechanisms of PROTACs and their application in targeting tumor-related targets. We have listed several representative PROTACs based on CRBN, VHL, MDM2, or cIAP1 E3 ligases, and PROTACs that are undergoing anti-cancer clinical trials. In addition, the limitations of the current research, as well as the future research directions are described to improve the PROTAC design and development for cancer therapy. Full article

(This article belongs to the Special Issue Past, Present and Future of Novel Therapeutic Modalities in Development for Targeted Protein Degradation)

► Show Figures

Figure 1

15 pages, 3059 KiB

Open AccessReview

Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System

by Sridhar Radhakrishnan, Oskar Hoff and Markus K. Muellner

Molecules 2022, 27(23), 8119; https://doi.org/10.3390/molecules27238119 - 22 Nov 2022

Cited by 3 | Viewed by 6238

Abstract

Bivalent proximity-inducing compounds represent a novel class of small molecule therapeutics with exciting potential and new challenges. The most prominent examples of such compounds are utilized in targeted protein degradation where E3 ligases are hijacked to recruit a substrate protein to the proteasome via ubiquitination. In this review we provide an overview of the current state of E3 ligases used in targeted protein degradation, their respective ligands as well as challenges and opportunities that present themselves with these compounds. Full article

(This article belongs to the Special Issue Past, Present and Future of Novel Therapeutic Modalities in Development for Targeted Protein Degradation)

► Show Figures