Degrader-antibody conjugates (DACs) are novel entities that combine a proteolysis targeting chimera (PROTAC) payload with a monoclonal antibody some type of chemical linker. This review provides a current summary of the DAC field. Many general aspects associated with the creation and biological performance of traditional cytotoxic antibody-drug conjugates (ADCs) are initially presented. These characteristics are subsequently compared and contrasted with related parameters that impact DAC generation and biological activity. Several examples of DACs assembled from both the scientific and the patent literature are utilized to highlight differing strategies for DAC creation, and specific challenges associated with DAC construction are documented. Collectively, the assembled examples demonstrate that biologically-active DACs can be successfully prepared using a variety of PROTAC payloads which employ diverse E3 ligases to degrade multiple protein targets.
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http://dx.doi.org/10.1039/d2cs00141a | DOI Listing |
Theranostics
January 2025
Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Proteolysis Targeting Chimeras (PROTACs) are bifunctional compounds that have been extensively studied for their role in targeted protein degradation (TPD). The capacity to degrade validated or undruggable targets provides PROTACs with significant potency in cancer therapy. However, the clinical application of PROTACs is limited by their poor potency and unfavorable pharmacokinetic properties.
View Article and Find Full Text PDFPharmacol Ther
November 2024
Drug Discovery Unit (DDU), Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT), Vellore 632014, India. Electronic address:
Targeted protein degradation (TPD) has emerged as a prominent and vital strategy for therapeutic intervention of cancers and other diseases. One such approach involves the exploration of proteolysis targeting chimeras (PROTACs) for the selective elimination of disease-causing proteins through the innate ubiquitin-proteasome pathway. Due to the unprecedented achievements of various PROTAC molecules in clinical trials, researchers have moved towards other physiological protein degradation approaches for the targeted degradation of abnormal proteins, including lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), molecular glue degraders, and other derivatives for their precise mode of action.
View Article and Find Full Text PDFJ Med Chem
September 2024
Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
Herein, we discuss advancements in the field of a unique class of antibody-drug conjugates (ADCs) named molecular glue-antibody conjugate (MAC). ADCs traditionally employ cytotoxic agents as payloads, and this approach has been used in all approved ADCs to treat cancer. Complementary to this approach, proteolysis targeting chimera (PROTAC) degrader antibody conjugates (DACs) provide a unique opportunity to deliver these bifunctional agents to tumors by using antibodies as a delivery mechanism to overcome the bioavailability issues encountered by PROTAC payloads.
View Article and Find Full Text PDFSci Bull (Beijing)
June 2024
State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Changping Laboratory, Beijing 102206, China. Electronic address:
Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted, but are of great clinical significance. According to statistics, over 80% of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods. In recent years, with the advancement of basic research and new technologies, the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets.
View Article and Find Full Text PDFEur J Med Chem
March 2024
Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China. Electronic address:
The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for the treatment of cancer and other diseases. PROTACs have demonstrated significant advantages in targeting undruggable targets and overcoming drug resistance. However, despite the efficient degradation of targeted proteins achieved by PROTACs, they still face challenges related to selectivity between normal and cancer cells, as well as issues with poor membrane permeability due to their substantial molecular weight.
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