Protein Degradation-Based Drug Discovery (PDBDD) Approach: Proteolysis Targeting Chimeras (PROTACs)

Dear Colleagues,

Protein degradation-based drug discovery (PDBDD) via proteolysis targeting chimeras (PROTACs) represents a paradigm-shifting approach in small molecule drug discovery and development toward novel medications for some severe human diseases, particularly anticancer agents. Despite the fact that development of protein degraders is still at an early stage, PROTACs and related molecules capable of selectively inducing targeted protein degradation by the ubiquitin–proteasome system offer one of the most appealing therapeutic strategies with potential advantages over traditional occupancy-based inhibitors in various aspects, such as superior target specificity, better efficacy at lower dose, fewer side effects, overcoming drug resistance and modulating “undruggable” drug targets. PROTACs are typically heterobifunctional small molecules which are made up of three portions including targeting the protein of interest (POI), an E3 ligand component, which recruits the E3 ligase to associate with the target protein, and a critical chemical linker, which conjugates the E3 ligand component to the ligand bound to the target protein. These degraders can recruit cellular protein degradation machinery to the proximity of ubiquitinated proteins and ultimately degrade the target protein by the proteasome. The degrader toolbox built from both academic and pharmaceutical industry settings is growing rapidly. Numerous small and large pharmaceutical companies are now competing by investing this attractive technology on various target-based small molecule protein degraders toward first-in-class medications. According to recent news reported in Nature Reviews Drug Discovery in 2021, one PROTAC-tracking database now lists more than 1600 publicly disclosed heterobifunctional small molecule degraders, acting on more than 100 drug targets. Excitingly, several targeted protein degraders crowd into the clinic, and at least 15 targeted degraders spinning from heterobifunctional PROTACs to molecular glues are anticipated to be tested on patients at different stages of human clinical trials by the end of 2021. The top runners advancing into human clinical trial phase II and phase I include androgen receptor degraders ARV-110, ARV-766 and AR-LDD, estrogen receptor degrader ARV-471, BCL-XL degrader DT2216, IRAK4 degraders KT-474 and KT-413, STAT3 degrader KT-333, BTK degraders NX-2127 and NX-5948, TRK degrader CG001419, and BRD9 degraders CFT8634 and FHD-609. This Special Issue aims to provide a forum for the dissemination of the latest information on targeted protein degradation and new PROTAC molecules, including both perspectives and research findings associated with PDBDD.

As the Guest Editor, I would like to thank all the authors for their tremendous effort, dedication, and excellent contribution to this Special Issue on “Protein Degradation-Based Drug Discovery (PDBDD) Approach: Proteolysis Targeting Chimeras (PROTACs)”. I hope that this issue will serve as a key reference work for medicinal chemists, chemical biologists, pharmacologists, and other research investigators engaged or interested in protein degradation and target-based drug discovery and development.

Prof. Dr. Jia Zhou
Guest Editor

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.

• protein degradation-based drug discovery (PDBDD)
• proteolysis targeting chimeras (PROTACs)
• targeted protein degradation
• protein degraders
• drug discovery and development
• synthetic molecules
• anticancer agents
• drug targets and mechanisms
• ubiquitin–proteasome system
• E3 ligases
• E3 ligands
• PROTAC linkers
• target-based drug discovery
• cancer therapies
• drug resistance
• modulating “undruggable” drug targets
• first-in-class medications