TAC‐tics for Leveraging Proximity Biology in Drug Discovery DOI

Dhanusha A. Nalawansha,

Kyle Mangano,

Willem den Besten

et al.

ChemBioChem, Journal Year: 2023, Volume and Issue: 25(4)

Published: Nov. 28, 2023

Abstract Chemically induced proximity (CIP) refers to co‐opting naturally occurring biological pathways using synthetic molecules recruit neosubstrates that are not normally encountered or enhance the affinity of interactions. Leveraging biology through CIPs has become a rapidly evolving field and garnered considerable interest in basic research drug discovery. PROteolysis TArgeting Chimera (PROTAC) is well‐established CIP modality induces between target protein an E3 ubiquitin ligase, causing degradation via ubiquitin‐proteasome system. Inspired by PROTACs, several other modalities have emerged modulate both proteins RNA over recent years. In this review, we summarize critical advances opportunities field, focusing on degraders, degraders non‐degrader such as post‐translational modification (PTM) protein‐protein interaction (PPI) modulators. We envision these emerging proximity‐based will be valuable resources for therapeutic discovery future.

Language: Английский

Utilizing aptamers in targeted protein degradation strategies for disease therapy DOI

Li Lin,

Songbo Xie,

Jun Zhou

et al.

The Journal of Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

Abstract Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy, offering the potential to reduce disease‐causing proteins that have traditionally been challenging target using conventional small molecules. Despite significant advances made with TPD technologies, challenges such high molecular weight, difficulties in identifying suitable ligands, suboptimal absorption, and metabolic instability remain unresolved. Recently, aptamers – single‐stranded DNA or RNA oligonucleotides known for their specificity affinity targets introduced novel opportunities expand scope of TPD, strategy now referred aptamer‐based TPD. This approach demonstrated considerable promise treating various diseases, cancer ocular disorders. For example, an aptamer‐proteolysis‐targeting chimera (PROTAC) conjugate (APC) improved tumor targeting reduced toxicity breast model, vascular endothelial growth factor‐degrading (VED)‐lysosome‐targeting (LYTAC) molecule effectively inhibited abnormal retinal diseases. These examples highlight practical relevance advancing drug discovery efforts. In this review we provide comprehensive overview latest strategies, including proteolysis‐targeting lysosome‐targeting chimeras, emphasizing applications, benefits, well must be overcome fully harness clinical potential. © 2025 The Pathological Society Great Britain Ireland.

Language: Английский

Citations

0
Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD based CRBN binder DOI Creative Commons

Seulki Park,

Akshay D. Takwale,

Jieun Lee

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117642 - 117642

Published: April 1, 2025

Targeting undruggable proteins by inducing proximity between E3 ligase and their substrates has emerged as an innovative strategy for tackling challenging diseases. In this study, we identified a novel GSPT1 degrader, 4a (KMG-1068), through screening of our in-house small molecule library. Treatment with demonstrated significant anti-proliferative activity across multiple cell lines, which was diminished co-treatment MLN4924, suggesting the involvement Cullin-containing complex. Quantitative proteomic analysis indicated that predominantly induces degradation GSPT1/2. We further validated 4a-mediated GSPT1/2 is dependent on both CUL4 CRBN. Moreover, forms ternary complex CRBN GSPT1/2, albeit weaker binding affinity compared to reported molecular glues. BRET assays competition pomalidomide binds C-terminal IMiD site CRBN, leading GSPT1. Despite lacking characteristic glutarimide moiety present in other CRBN-based glue degraders, interacts effectively Structural characterization analog synthesis underscored importance specific structural features engagement, degradation, effects, establishing promising degrader therapeutic potential.

Language: Английский

Citations

0
Structure-Guided Design of ISOX-DUAL-Based Degraders Targeting BRD4 and CBP/EP300: A Case of Degrader Collapse DOI Creative Commons
Anthony K. Edmonds, Dimitrios-Ilias Balourdas, Graham P. Marsh

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Degraders with dual activity against BRD4 and CBP/EP300 were designed. A structure-guided design approach was taken to assess test potential exit vectors on the inhibitor, ISOX-DUAL. Candidate degrader panels revealed that VHL-recruiting moieties could mediate dose-responsive ubiquitination of BRD4. panel CRBN-recruiting thalidomide-based degraders unable induce or degradation target proteins. High-resolution protein cocrystal structures an unexpected interaction between thalidomide moiety Trp81 first bromodomain The inability form a ternary complex provides rationale for lack these compounds, some which have remarkable affinities close those (+)-JQ1, as low 65 nM in biochemical assay, vs 1.5 μM their POI ligand, Such "degrader collapse" may represent under-reported mechanism by putative molecules are inactive respect degradation.

Language: Английский

Citations

0
Late‐Stage C−H Activation of Drug (Derivative) Molecules with Pd(ll) Catalysis DOI Creative Commons
Su Yong Shim

Chemistry - A European Journal, Journal Year: 2023, Volume and Issue: 29(71)

Published: Oct. 17, 2023

Abstract This review comprehensively analyses representative examples of Pd(II)‐catalyzed late‐stage C−H activation reactions and demonstrates their efficacy in converting bonds at multiple positions within drug (derivative) molecules into diverse functional groups. These transformative hold immense potential medicinal chemistry, enabling the efficient selective functionalization specific sites molecules, thereby enhancing pharmacological activity expanding scope candidates. Although notable articles have focused on drug‐like using transition‐metal catalysts, reviews specifically focusing Pd(II) catalysts are required owing to prominence as most widely utilized metal for ability introduce a myriad groups bonds. The utilization Pd‐catalyzed methodologies impressive success introducing various groups, such cyano (CN), fluorine (F), chlorine (Cl), aromatic rings, olefin, alkyl, alkyne, hydroxyl with high regioselectivity functional‐group tolerance. breakthroughs serve invaluable tools discovery development, offering strategic options optimize candidates drive exploration innovative therapeutic solutions.

Language: Английский

Citations

10
TAC‐tics for Leveraging Proximity Biology in Drug Discovery DOI

Dhanusha A. Nalawansha,

Kyle Mangano,

Willem den Besten

et al.

ChemBioChem, Journal Year: 2023, Volume and Issue: 25(4)

Published: Nov. 28, 2023

Abstract Chemically induced proximity (CIP) refers to co‐opting naturally occurring biological pathways using synthetic molecules recruit neosubstrates that are not normally encountered or enhance the affinity of interactions. Leveraging biology through CIPs has become a rapidly evolving field and garnered considerable interest in basic research drug discovery. PROteolysis TArgeting Chimera (PROTAC) is well‐established CIP modality induces between target protein an E3 ubiquitin ligase, causing degradation via ubiquitin‐proteasome system. Inspired by PROTACs, several other modalities have emerged modulate both proteins RNA over recent years. In this review, we summarize critical advances opportunities field, focusing on degraders, degraders non‐degrader such as post‐translational modification (PTM) protein‐protein interaction (PPI) modulators. We envision these emerging proximity‐based will be valuable resources for therapeutic discovery future.

Language: Английский

Citations

9