Mechanistic Insights: A Leap Forward in Molecular Glue Technology

The CELMoDs library compounds exploit the unique structure of the CRBN protein, particularly its thalidomide binding domain (TBD) and Lon protease-like domain (Lon). By stabilizing CRBN in its closed conformation, these compounds enhance the proximity and interaction between these domains, thereby optimizing the binding and degradation of specific proteins. Notable examples from scientific literature include CC-92480 (Mezigdomide) and CC-220 (Iberdomide), which effectively bind to CRBN’s sensor loop, achieving remarkable therapeutic outcomes.

Advanced Design and Unique Features

• Curated for CRBN Modulation: Unlike generic small molecule libraries, the CELMoDs library is specifically tailored for CRBN stabilization. This precision enables selective degradation pathways that other libraries cannot achieve.
• Dual Functionality: Compounds in the CELMoDs library serve dual roles:
  • Acting as direct molecular glues to stabilize CRBN in its functional conformation.
  • Serving as potential warheads for designing novel PROTACs.
• High Ligand Efficiency (LE): Compounds are pre-screened through advanced molecular docking to ensure optimal binding efficiency at the thalidomide binding site, significantly accelerating the early stages of drug discovery.

Comprehensive Medicinal Chemistry Insights

The CELMoDs library offers researchers a versatile toolkit for hypothesis generation and testing in targeted protein degradation. Compounds are MedChem-compatible, providing an invaluable resource for:

• Direct screening of potential molecular glues.
• Development of alternative warheads.
• Medicinal chemistry insights into CRBN-targeted drug development.

Structure and Composition

The CELMoDs library comprises 1256 compounds divided into four distinct categories to optimize discovery pipelines:

1. Long Core: 61 compounds closely aligned with optimal docking modes, forming robust interactions with TBD and Lon domains.
2. Long Diversity: 576 diverse compounds exploring broader chemical spaces while maintaining interactions with both domains.
3. High LE Core: 293 compounds with high ligand efficiency, predominantly occupying thalidomide’s site in TBD.
4. High LE Diversity: 326 diverse compounds loosely related to high ligand efficiency docking modes.

Applications and Therapeutic Potential

The CELMoDs library is ideal for researchers aiming to advance targeted protein degradation therapies in oncology, neurodegenerative diseases, and autoimmune conditions. The library's focus on CRBN modulation opens new avenues for therapeutic interventions, particularly in cases where selective degradation of pathogenic proteins can provide groundbreaking clinical outcomes.

Scientific Legacy and Future Directions

By leveraging innovative design and rigorous pre-screening, the CELMoDs library empowers researchers to pioneer next-generation therapies. Its robust framework not only accelerates the discovery of novel molecular glues but also contributes to a deeper understanding of CRBN’s role in cellular processes. As a result, the CELMoDs library establishes itself as an indispensable resource for modern drug discovery.

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