E3 ligase complex

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. PROTACs consist of a ligand for E3 ligase (E3 ligase binder), a linker and a ligand (mostly small-molecule inhibitor) for protein of interest（target binder）. Upon binding to the target protein, the PROTACs can recruit E3 for target protein ubiquitination, which is subjected to proteasome-mediated degradation.

Although there are more than 600 E3 ubiquitin ligases, only several with small molecule ligands have been used for designing PROTACs, including Skp1-Cullin-F box complex containing Hrt1 (SCF), Von Hippel-Lindau tumor suppressor (VHL), Cereblon (CRBN), inhibitor of apoptosis proteins (IAPs), and mouse double minute 2 homolog (MDM2).

MCE carefully prepared a unique collection of 174 ligands for E3 ligase, which have been reported to be used in PROTAC design. MCE E3 ligase ligand library is a useful tool for PROTAC development.

Targeted protein degradation(TPD) is a novel and promising approach to new drug discovery and development. It shows great potential for treating diseases with “undruggable” pathogenic protein targets and for overcoming drug resistance. Molecular glues and PROTACs are both targeted protein degraders that have attracted the most attention.

Molecular glues are small molecular degraders that mainly induce novel interaction between an E3 ligase and a target protein to form a ternary complex, leading to protein ubiquitination and subsequent proteasome degradation. Compared with PROTACs, molecular glues generally possess more favorable drug-like properties, such as lower MW, higher cell permeability, and better oral absorption. Molecular glues are emerging as a promising new therapeutic strategy.

MCE supplies a unique collection of 105 molecular glues which target various proteins. MCE Molecular Glue Compound Library is a useful tool to conduct scientific research and disease mechanism study.

Targeted Protein Degradation (TPD) is a novel and promising approach to drug development. It shows great potential for targeting proteins traditionally considered "undruggable" due to the lack of enzymatic function and absence of binding sites by tagging them for degradation or recruiting natural degradation mechanisms.

Molecular glues are a type of small-molecule degraders that primarily induce novel interactions between E3 ubiquitin ligases and target proteins, forming ternary complexes that lead to protein ubiquitination and subsequent proteasomal degradation. Compared with PROTACs, molecular glues generally have lower molecular weights, higher cell permeability, and better drug-like properties. Additionally, the design of molecular glues is relatively simple, without the requirements for complex linkers and ligand optimization. As a result, molecular glues have gradually emerged as a promising therapeutic approach for various diseases.

Multiple types of molecular glues have been reported previously. Analysis of co-crystal complex structures reveals that CRBN-related molecular glues are more versatile. Therefore, MCE researchers select active molecules related to these targets as probes for artificial intelligence (AI) screening.Subsequently, molecular docking technology was used to verify whether the screened molecules retained the key pharmacophore features. Ultimately, we obtained 317 molecular glue analogs, and these compounds serve as powerful tools for the research of molecular glues.

CRBN, namely cereblon, is the substrate recognition subunit of the E3 ubiquitin ligase complex in the ubiquitin-proteasome system. A CRBN ligand library refers to a collection of numerous fragments that can specifically bind to the CRBN protein.

These ligands are mostly designed based on validated CRBN-binding warheads and modified through AI-driven molecular generation optimization systems. They not only include classic lenalidomide-derived structures but also cover novel non-lenalidomide scaffolds. After drug-likeness filtering, these ligands exhibit structural diversity and favorable druggable properties. They can be further optimized and modified to facilitate the development of novel molecular glue degraders, accelerate the discovery of molecular glues that induce interactions between CRBN and new substrate proteins, and enable the exploration of novel CRBN substrates for identifying previously unknown CRBN-binding proteins.

MCE compiles 125 fragments that can specifically bind to the CRBN protein, with molecular weights ranging from 200 to 500. Compounds developed based on the library ligands target multiple disease targets such as cancer and autoimmune diseases, further advancing the development of Molecular Glues and PROTACs therapeutic agents.

Sulfonyl fluoride (-SO₂F) overcomes the bottleneck of target selectivity in traditional covalent warheads through its unique chemical and biological properties, which rely heavily on cysteine (Cys) residues. Featuring high stability and tunable electrophilicity under physiological conditions, it can target a wide range of nucleophilic residues including lysine (Lys), tyrosine (Tyr), serine (Ser), and histidine (His). It offers the advantages of a broader druggable space, lower off-target risks, and long-lasting efficacy, with numerous reported cases in the research of covalent inhibitors, Molecular glue, PROTACs, and chemical biology probe development.

MCE constructs a highly diverse sulfonyl fluoride fragment library based on the reactivity, stability and physiological compatibility of sulfonyl fluoride. The library contains 1000 efficiently synthesized and stable sulfonyl fluoride fragments, which ensure precise reactivity of the warhead and retain sufficient derivatization space for subsequent optimization. Combined with the modular strategy of SuFEx click chemistry, it enables versatile modification of compounds and functionalization of complex molecules, improves the efficiency of structural optimization and rapidly expands druggability, making it suitable for high-throughput probe and custom covalent library construction. It provides an efficient research tool for the development of broad-spectrum covalent inhibitors targeting Lys/Tyr/Ser/His, covalent PROTACs for E3 ligases and chemical biology probe development, meeting the requirements of modern drug research for high throughput, high success rate and high derivatization potential.

This library contains 1,162 sulfonyl fluoride fragments with high structural diversity, favorable drug-like properties and tunable electrophilicity. It is well suited for precise targeting of non-Cys residues and meets the criteria of simple structure and high derivatization potential. It effectively improves