Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Heterobifunctional degraders (also known as proteolysis-targeting chimeras or PROTACs) have emerged in drug discovery as an alternative therapeutic modality for targeting disease-causing proteins that are challenging to modulate with standard protein inhibitors. Almost all current PROTACs under clinical studies use the E3 ligase cereblon (CRBN) to hijack the ubiquitin-proteasome system. In this study, we used high-throughput experimentation to identify new conditions to access carbon-carbon bonds on our CRBN warheads. These efforts led to the discovery that alkyl-connected CRBN binders demonstrate improved cell permeability and reduced neosubstrate activity when compared with their amide counterparts. To further demonstrate the value of this protocol and the resulting alkyl connection point, these conditions were utilized as a final synthetic step to produce a heterobifunctional BRD4 degrader with an improved CRBN neosubstrate selectivity profile compared to its amide counterpart.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c03157 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis.
Arch Pharm Res
September 2025
College of Pharmacy, Hanyang University, Ansan, 15588, Republic of Korea.
c-Jun N-terminal kinases (JNKs), a subfamily of mitogen-activated protein kinases (MAPKs), are key mediators of cellular responses to environmental stress, inflammation, and apoptotic signals. The three isoforms-JNK1, JNK2, and JNK3 exhibit both overlapping and isoform-specific functions. While JNK1 and JNK2 are broadly expressed across tissues and regulate immune signaling, cell proliferation, and apoptosis, JNK3 expression is largely restricted to the brain, heart, and testis, where it plays a crucial role in neuronal function and survival.
View Article and Find Full Text PDFInjectable PROTAC-loaded hydrogel remodels the tumor microenvironment to potentiate radio-immunotherapy.
J Control Release
September 2025
Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People's Republic of China. Electronic address:
Radiotherapy (RT) is a key component of comprehensive cancer treatment regimens; nevertheless, its concomitant immunosuppression may diminish therapeutic efficacy. In this study, we developed an injectable hydrogel system for the local delivery of PROteolysis TArgeting Chimeras (PROTACs), achieved by loading tumor cell membrane-fused liposome nanoparticles to enhance the anti-tumor effect. The system targeted Bromodomain-containing protein 4 (BRD4), and combined treatment with RT promoted DNA damage, reduced DNA repair and decreased tumor cell proliferation and survival.
View Article and Find Full Text PDFContemporary trends in targeted protein degradation for neurodegenerative diseases.
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 PDFPROTACs therapeutically target the polyglutamine androgen receptor in spinal and bulbar muscular atrophy models.
Neurotherapeutics
September 2025
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:
Spinal and bulbar muscular atrophy (SBMA) is a CAG/polyglutamine (polyQ) repeat expansion disorder in which the mutant androgen receptor (AR) protein triggers progressive degeneration of the neuromuscular system in men. As the misfolded polyQ AR is the proximal mediator of toxicity, therapeutic efforts have focused on targeting the mutant protein, but these prior efforts have met with limited success in SBMA patients. Here, we examine the efficacy of small molecule AR proteolysis-targeting chimera (PROTAC) degraders that rapidly and potently promote AR ubiquitination and degradation by the proteasome.
View Article and Find Full Text PDFCa/Calmodulin-Dependent Protein Kinase II (CaMKII)-Targeted Drug Discovery: Challenges and Strategies.
Ageing Res Rev
September 2025
Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China; Laboratory of Naturel Medicine for drug discovery, School of Pharmacy, China Medical University, Shenyang, 110122, China. Electronic address:
Calcium (Ca)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is an emerging drug target for age-related diseases. It is a multifunctional kinase with complex activation modes, numerous isoforms, broad tissue distribution, and a dual role in health and disease. In particular, its isoforms share a high degree of conservation within the catalytic and regulatory domains, with only minor differences confined to the linker region.
View Article and Find Full Text PDF