Lead optimization

Linkers, as key structural units in PROTAC molecules that connect the two functional ends, not only determine the overall molecular conformation and spatial compatibility but also directly influence the stability of the ternary complex, as well as cellular permeability and degradation efficiency. In recent years, with the widespread application of click chemistry in medicinal chemistry, the incorporation of bioorthogonal reactive groups such as azides (-N₃) into PROTAC linker design has become an emerging research focus, providing an important tool for modular assembly and rapid structural optimization.

The MCE Azide PROTAC Linker Library contains 190 linkers specifically designed for targeted protein degradation molecule design and optimization. These linkers serve as efficient “click handles,” enabling rapid and highly selective covalent coupling with alkyne reaction partners, thereby facilitating modular assembly and structural diversification of PROTAC molecules. In drug development, this design not only improves the efficiency of molecular construction but also significantly accelerates the screening and optimization of lead compounds. Meanwhile, by tuning linker properties such as length, flexibility, and polarity, the ability to form ternary complexes and degradation activity can be optimized.

In PROTAC drug development, linkers are often one of the key variables determining drug-likeness and degradation efficiency. Since PROTAC systems must simultaneously satisfy target protein binding, E3 ligase recruitment, and intracellular spatial conformational matching, their structural design is essentially a multi-parameter optimization problem. Differences in linker rigidity, flexibility, and spatial extension can significantly influence the formation pathway and stability of the ternary complex, leading to substantial variations in degradation activity. Therefore, the development of linker systems with modular tunability and high structural expandability has become an important direction in PROTAC optimization.

The MCE Alkyne PROTAC Linker Library contains 231 linkers based on terminal and internal alkyne scaffolds, forming a highly derivatizable linker module system. These linkers serve as standardized building blocks for rapid assembly and iterative optimization of PROTAC molecules, and support efficient conjugation with azide-containing functional groups via click chemistry. In practical drug development, this type of structure not only facilitates the construction of diverse linker space libraries, accelerating lead compound screening, but also enables systematic tuning of molecular geometry and physicochemical properties, thereby improving ternary complex stability and targeted protein degradation efficiency.

Chirality can significantly influence drug–target affinity, subtype selectivity, and toxicological profiles. The thalidomide tragedy highlights the profound biological consequences of stereochemistry, making stereochemical evaluation essential in early drug discovery. Three Nobel Prizes in Chemistry—in 2001, 2021, and 2026—have advanced our understanding of chirality, from asymmetric catalysis and stereoselective synthesis to asymmetric autocatalysis and nonlinear effects that explain the propagation and amplification of chiral signals.

Enantiomers (R/S) can exhibit distinct target-binding affinities, subtype selectivity, and pharmacokinetic properties. This library supports enantiomer-specific binding studies using affinity selection–mass spectrometry (AS-MS) and other screening platforms.

Library Highlights: Comprising 2,792 structurally diverse small molecules, the library offers broad chemical space coverage and lead-like physicochemical properties. It supports high-throughput screening across therapeutic targets, hit identification, and preliminary structure–activity relationship (SAR) studies. Complementary stereochemical characterization services facilitate seamless integration into lead optimization programs.

Small molecule covalent inhibitors, or irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity, such that covalent warheads can target rare residues of a particular target protein, thus leading to the development of highly selective inhibitors and achieving a more complete and continued target occupancy in living systems. In recent years, the distinct strengths of covalent inhibitors in overcoming drug resistance had been recognized. However, toxicity can be a real challenge related to this class of therapeutics due to their potential for off-target reactivity and has led to these drugs being disfavored as a drug class. The drug design and optimization of covalent inhibitors has become a hot spot in drug discovery.

MCE Lead-like Covalent Screening Library offers a valuable resource of 1,049 lead-like compounds with commonly used covalent warheads. These warheads, such as acrylamide, activated terminal alkyne, acyloxymethyl ketone, and boronic acid, are capable of reacting with specific amino acid residues, including cysteine, lysine, serine, and histidine. The inclusion of these reactive warheads in the library allows researchers to explore the potential of covalent inhibition, a powerful approach in drug discovery.

In drug discovery and development (R&D) area, target binding and druggability optimization are core processes. Among these attributes, high solubility is critical for a compound to achieve druggability, as it directly impacts the progress of drug R&D. Superior solubility ensures the rapid dissolution and uniform distribution of drug molecules in vivo, thereby enhancing bioavailability and effectively mitigating issues such as suboptimal efficacy, increased dosage requirements, or exacerbated toxic and side effects arising from insufficient solubility.

From the perspective of medicinal chemistry, high-solubility drug fragments serve as high-quality "molecular building blocks". Based on these fragments, lead compounds with potential druggability can be rapidly screened out, which significantly shortens the drug R&D cycle and reduces R&D costs. Meanwhile, the high-solubility drug fragment library can provide diverse options for drug development in different therapeutic areas, offer solutions for the solubility defects of existing clinical drugs, and facilitate the development of novel, highly effective targeted drugs with higher bioavailability and better safety profiles.

MCE has collected and compiled 2,526 experimentally validated small-molecule fragments with high solubility. These fragments can be directly used for drug molecular design, providing high-quality pre-validated solubility fragments that significantly improve the efficiency of lead compound screening and accelerate the progress of drug R&D.

Kidneys are one of the vital organs in the human body. Due to their exposure to higher concentrations of circulating drugs or metabolites, they are highly susceptible to drug-induced renal injury (DIRI). According to statistics, drug-induced kidney injury accounts for approximately 20% of nephrotoxicity reports and can lead to acute kidney injury (AKI), chronic kidney disease (CKD), or even end-stage renal disease (ESRD). Early detection of drug nephrotoxicity is crucial for preventing irreversible kidney damage. Research into its mechanisms can help optimize clinical medication by adjusting dosages or avoiding combinations of nephrotoxic drugs. Additionally, predicting drug-induced nephrotoxicity in early drug development can reduce the risk of late-stage R&D failure.

MCE offers 160 nephrotoxicity compounds that have been clearly reported by the FDA to be associated with kidney injury. This library can be used for studying molecular mechanisms of nephrotoxicity or developing novel biomarkers.

A diverse compound library with favorable ADMET properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity) is crucial in drug discovery. Early evaluation of ADMET properties allows for the exclusion of molecules with unfavorable profiles at the initial stages, thereby reducing the risk of late-stage development failures, lowering R&D costs, and accelerating optimization of lead compounds. Based on predictions from ADMET-related AI algorithms, the compounds in this library are predicted to exhibit favorable oral bioavailability (F > 30%), reasonable plasma protein binding (PPB < 98%), minimized CYP3A4 inhibition potential (inhibition probability < 50%, CYP3A4 is the most critical drug-metabolizing enzyme in the cytochrome P450 family) , low toxicity profiles, with 140 potentially toxic substructures pre-identified and excluded via substructure searching to eliminate compounds containing hazardous fragments. The diversity library enables broad applicability in high-throughput screening (HTS) and high-content screening (HCS).

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.

Macrocyclic scaffolds are increasingly valued in modern drug discovery for their exceptional activity against undruggable targets (proteases, kinases, PPIs). 2026 marks a key commercial breakthrough for oral macrocyclic peptides: enlicitide, the world’s first oral PCSK9 macrocyclic peptide, has received FDA approval. Macrocyclic candidates targeting KRAS and other classic undruggable targets have also entered clinical development, validating macrocyclization as an effective strategy to overcome druggability barriers.

Two core R&D directions lead current macrocyclic drug design: AI-driven de novo generation and structural optimization of small-molecule macrocycles, and macrocyclic peptides based on sequence design and conformational engineering. Macrocycle druggability hinges on embedded linkers, which determine cyclization efficiency, final conformation and drug-like properties. Bifunctional reaction orthogonality is the core linker selection criterion. Our linker library enables stepwise intramolecular cyclization with suppressed side reactions, accommodates varied ring sizes, and covers three key reaction systems: amide condensation, nucleophilic substitution and CuAAC click chemistry.

Built on classical macrocyclization systems, the library is processed through reaction classification, bifunctional orthogonality evaluation, novelty clustering and redundancy removal, with PROTAC long-chain and ADC cleavable linkers explicitly excluded. Featuring rigid, semi-rigid and flexible scaffolds, it is widely applicable to small-molecule macrocycle synthesis and linear peptide cyclization.