undruggable

Macrocycles, molecules containing 12-membered or larger rings, are receiving increased attention in small-molecule drug discovery. The reasons are several, including providing access to novel chemical space, challenging new protein targets, showing favorable ADME- and PK-properties. Macrocycles have demonstrated repeated success when addressing targets that have proved to be highly challenging for standard small-molecule drug discovery, especially in modulating macromolecular processes such as protein–protein interactions (PPI). Otherwise, the size and complexity of macrocyclic compounds make possible to ensure numerous and spatially distributed binding interactions, thereby increasing both binding affinity and selectivity.

MCE offers a unique collection of 464 macrocyclic compounds which can be used for drug discovery for high throughput screening (HTS) and high content screening (HCS). MCE Macrocyclic Compound Library is a useful tool for discovering new drugs, especially for “undruggable” targets and protein–protein interactions.

MCE 18 stands for Medicinal Chemistry Evolution 2018. This metric was established based on structural data of 28,161 patented lead molecules, 1,370 marketed innovative drugs, and nearly 30,000 investigational candidates from preclinical to Phase III stages across 23 major global pharmaceutical companies from 1950 to 2018. After scaffold clustering analysis, a scoring model was constructed by integrating five three dimensional scaffold characteristics, including aromatic rings (AR), non aromatic heterocycles (NAR), chiral centers (CHIRAL), spirocycles (SPIRO), and the sp³ carbon ratio in cyclic and acyclic moieties, enabling quantitative assessment of molecular scaffold novelty and three dimensional complexity.

According to the score distribution of patented molecules, the top 25% of the original patent dataset was defined as the high novelty region. MCE 18 high scoring compounds selected based on this criterion can effectively avoid scaffold patent conflicts and intellectual property risks from the source. Molecules in this range typically feature a high sp³ carbon ratio, abundant chiral centers, spirocycles, and fused heterocycles with prominent three dimensional conformations. Their spatial properties allow precise matching to complex non traditional undruggable target pockets such as PPI interfaces and allosteric sites, making them ideal structural types for early stage screening of First in class drugs.

MCE‑18 Novelty Focused drug‑Like library strictly selects molecules from the aforementioned high scoring range, containing more than 10,000 premium drug like molecules with highly diverse scaffolds and rich 3D diversity. It can be used for high throughput screening of well established targets such as kinases, GPCRs, and proteases, and is especially suitable for hit identification in allosteric modulation, protein–protein interactions, and various undruggable orphan targets, fully supporting early stage drug discovery for cutting edge innovat

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

KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is one of the most important oncogenic driver genes in oncology, with high mutation frequencies in pancreatic cancer, non‑small cell lung cancer, and colorectal cancer. For a long time, KRAS was considered "undruggable" due to the lack of suitable small‑molecule binding pockets on its protein surface. In recent years, with the discovery of the switch‑II pocket and the successful approval of KRAS G12C inhibitors, KRAS‑targeted research has achieved groundbreaking progress, which has also spurred a wave of development targeting non‑G12C mutants such as G12D and G12V, as well as upstream and downstream regulatory factors including SOS1 and SHP2.

MCE KRAS Targeted Compound Library contains 79 small‑molecule compounds targeting the KRAS, serving as high‑quality research tools for mechanistic studies of KRAS‑mutant tumors, combination therapy development, resistance mechanism exploration, and high‑throughput drug screening, thereby providing robust support for KRAS‑targeted drug discovery.

Cyclic peptide library have advantages such as high affinity, high selectivity, and suitability for targeting protein–protein interactions. Through DEL synthesis technology, the library size can achieve hundreds of millions. DEL cyclic peptide library have advantages like low cost andhigh screeing efficiency, making them valuable for discovering lead compounds against challenging drug targets.

This cyclic peptide library is constructed with unnatural amino acids as building block, synthesized through DNA-compatible chemical reactions. Each cyclic peptide consist of six amino acids and constrained conformations such as side-chain cross-linking, disulfide bonds, and macrocyclization. These cyclic peptides exhibit significantly improved stability and druggability compared with linear peptides, filling the gap between small molecules and macromolecular biologics. Each cyclic peptide is uniquely conjugated to a DNA barcode sequence for molecular identification and sequencing decoding.

MCE’s cyclic peptide library has8 independent sub-libraries, with a total molecular diversity of 1.2 billion. It is constructed via multi-round combinatorial assembly of building blocks and diverse cyclization strategies, facilitating the discovery of cyclic peptide leads for undruggable targets.

The RNA-targeted bioactive compound library is a high-quality collection of small molecules specifically designed and curated to target RNA structures and functions. It is widely applied in cutting-edge drug discovery and life science research. Unlike traditional strategies that focus on protein targets, RNA-targeted compounds can directly modulate various functional RNA molecules by influencing their splicing, translation, stability, or structural conformation, thereby enabling precise intervention in key biological processes. In the field of drug development, these compounds provide a novel approach to addressing previously “undruggable” targets and have demonstrated significant potential in areas such as oncology, antiviral therapies, and neurodegenerative diseases. For example, by targeting disease-associated RNA structural domains or regulating the aberrant expression of non-coding RNAs, these compounds can effectively inhibit disease progression or restore normal cellular function. In mechanistic studies, RNA-targeted compounds serve as valuable chemical biology tools to elucidate the roles of RNA in gene expression regulation, cellular signaling pathways, and disease development.

The MCE RNA-targeted bioactive compound library contains 860 compounds, sourced from databases such as TargetRX Atlas and R-BIND. The library features excellent structural diversity and biological activity, making it suitable for high-throughput screening (HTS), target validation, phenotypic screening, and lead compound discovery. It represents a valuable resource for RNA-related research and innovative drug development.

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.

POI (Protein of Interest) refers to the target protein, namely the disease-causing protein or key functional protein that undergoes degradation or functional modulation in molecular glue-mediated processes. The Molecular Glue POI Library consists of a series of fragments that can specifically bind to different types of POIs. As key components of molecular glues, these ligands form stable interactions with target proteins, laying the foundation for molecular glues to induce the interaction between POIs and E3 ubiquitin ligases. The covered POIs include various types such as cancer-associated GSPT1, androgen receptors, and abnormally aggregated proteins linked to neurodegenerative diseases.

This fragment library can be applied to the screening and optimization of targeted protein degraders. By screening ligands with high affinity and strong selectivity for specific POIs from the library, core structures can be identified to develop novel molecular glues. For instance, optimization of ligands targeting GSPT1 has yielded molecular glue degraders with enhanced degradation activity. Since many POIs are difficult to drug due to the lack of traditional small-molecule binding pockets, some ligands in the POI Ligand Library can modulate such POIs by inducing protein-protein interactions, thereby further expanding the scope of drug discovery for undruggable targets.

MCE has compiled a POI Fragment Library comprising thousands of POI fragments with molecular weights ranging from 150 to 400. This compound library can be widely applied in Molecular Glue research and development.

Spirocyclic compounds, with rigid 3D structures, high Fsp³ and strong conformational restriction, are highly privileged scaffolds in small-molecule drug screening. They overcome drawbacks of planar aromatic compounds such as poor solubility, high off-target risks and weak druggability. Their orthogonal bicyclic geometry fits well into protein pockets, improving target affinity, subtype selectivity, metabolic stability and membrane permeability, making them ideal for hit identification against kinases, GPCRs, PPIs and other targets.

Spirocyclic scaffolds have been widely applied in oncology, antivirals, hypertension and CNS diseases, leading to many approved drugs and clinical candidates. SAR studies show that spiro-atom chirality, ring size and heteroatom substitution dominate bioactivity and selectivity, with the scaffold mainly serving as a conformational anchor. Azaspirocycles, spirooxindoles and spirosteranes target GPCRs, kinases, MDM2-p53 and PPIs. Approved drugs including irbesartan, spironolactone and rolapitant confirm their druggability, while revumenib and SAR405838 show promise against undruggable targets.

The MCE Spirocyclic Druglike Library contains over 1,000 diverse, stereospecific molecules selected by Lipinski’s rules. It covers privileged cores such as azaspirocycles, oxaspirocycles and spirooxindoles. These molecules bear rich chiral centers and distinct 3D orientations, reducing non-specific binding and enhancing screening efficiency. Featuring novel scaffolds, the library offers a highly innovative starting point for drug discovery.

DEL technology enables the simultaneous screening of millions or billions of compounds in a single tube by covalently linking each small molecule with a unique DNA sequence. Traditional DEL screening primarily focuses on identifying non-covalent binding molecules, where interactions with the target are reversible. In contrast, DNA‑encoded covalent library is an ultra‑high‑throughput screening library developed on the basis of conventional DNA‑encoded library technology. It incorporates controllable electrophilic covalent warheads capable of forming irreversible covalent bonds with amino acid residues at the active sites of target proteins, including Cys, Lys, Ser, Tyr, and others. This covalent binding enhances binding affinity, prolongs residence time at the target site, and has the potential to overcome challenges associated with traditional non-covalent inhibitors, such as drug resistance or off-target effects.

Each compound in the library contains both a binding domain and an electrophilic warhead. It first recognizes and binds to the target through non covalent interactions, and then forms a stable covalent bond with key amino acid residues to achieve irreversible inhibition. This library is specifically designed for the discovery of potent, long lasting, and highly selective covalent inhibitors, particularly for undruggable targets such as kinases, GPCRs, proteases, and mutant oncoproteins. Each molecule is uniquely labeled with a DNA barcode for molecular identification and sequencing decoding.

This library is an advanced and highly diverse collection, consists of 35 independent sub-libraries with a total scaleof 14 million compounds, It incorporates over 14 experimentally validated covalent warheads capable of targeting cysteine, lysine, arginine, aspartic acid and glutamic acid. This library is constructed with diverse drug like core scaffolds and integrated controllable covalent warheads, it features structural diversity, reaction spec