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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. Recently, a cereblon binding monovalent degrader called molecular glues has been used in new ADCs that we have coined the term molecular-glue antibody conjugates (MACs). In this article, we intend to review advancements made in the field of targeted delivery of cereblon-based molecular glue degraders.
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http://dx.doi.org/10.1021/acs.jmedchem.4c01289 | DOI Listing |
Future Med Chem
September 2025
Laboratory of Biomedical Chemistry, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
Eur J Med Chem
August 2025
Amity Institute of Pharmacy, Amity University Haryana, 122413, India. Electronic address:
Neurodegenerative diseases (NDs), including Alzheimer's, Huntington's, and Parkinson's disease, are associated with significant declines in cognitive function and mobility. The accumulation of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates is a key factor in the progression of these conditions. Unfortunately, traditional small-molecule drugs face major obstacles in effectively targeting these proteins.
View Article and Find Full Text PDFJ Med Chem
September 2025
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States.
Rational optimization of molecular glue degraders (MGD) remains a challenging and lengthy process even after identification of a promising scaffold. Unlike proteolysis targeting chimeras (PROTAC), MGDs rely on induced protein-protein interactions as opposed to direct binding in order to target a protein of interest for degradation. Here, we report the synthesis of MGDs targeting the transcription factor ZBTB11 guided by protein complex modeling.
View Article and Find Full Text PDFAcc Chem Res
September 2025
Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco 94158, United States.
ConspectusProtein-protein interactions (PPIs) play a key role in homeostasis and are often dysregulated in disease. PPIs were traditionally considered "undruggable" due to their flat surfaces and disordered domains. Recently, the identification of PPI stabilizers, or molecular glues (MGs), compounds that bind cooperatively to PPI interfaces, has provided a new direction for the field.
View Article and Find Full Text PDFActa Pharm Sin B
August 2025
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint damage, accompanied by the accumulation of plasma cells, which contributes to its pathogenesis. Understanding the genetic alterations occurring during plasma cell differentiation in RA can deepen our comprehension of its pathogenesis and guide the development of targeted therapeutic interventions. Here, our study elucidates the intricate molecular mechanisms underlying plasma cell differentiation by demonstrating that PRDX1 interacts with DOK3 and modulates its degradation by the autophagy-lysosome pathway.
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