Welcome to Your December Newsletter!
WuXi Discovery Services
Driving drug discovery through world-class capabilities, dedicated collaborative teams, and scientific excellence.
Evaluation of T Cell Engagers
T-cell engagers (TCEs) are a class of bispecific antibodies that can simultaneously target and bind to tumor cells and T cells, thereby activating T cells and mediating their cytotoxic effects on tumor cells. This dual binding mechanism allows T cells to accurately identify and attack tumor cells. TCEs have advantages of high specificity and strong immune responses in anti-tumor therapy. WuXi Biology has established a comprehensive in vitro and in vivo pharmacology platform to assist in the research and development of T cell engagers.
Targeted Protein Degradation Platform
Targeted protein degradation (TPD) technology has become one of the most promising methods to remove specific disease-related proteins using cellular self-destruction mechanisms. This technology is enabling researchers to pursue targets that were previously considered undruggable and to address the resistance issue of small molecule inhibitors.
Since 2016, WuXi AppTec has built a comprehensive TPD discovery service platform to investigate the full functional cycle of protein degraders – from binary/ternary complex formation to target ubiquitination and degradation. At the 7th Annual TPD & Induced Proximity Summit, we presented a poster demonstrating the capabilities of our TPD platform, highlighting TPD research strategies through relevant case studies.\
Discovery of Molecular Glues: Challenges & Opportunities
Molecular glues (MGs) are a class of small molecules that alter the surface properties of proteins to strengthen or induce protein-protein interactions (PPI), a process referred to as induced proximity. The best-established application of molecular glues is inducing targeted protein degradation (TPD). By inducing PPI between a target protein and an E3 ligase, a ternary complex consisting of “target protein/molecular glue/E3 ligase” is created.
Molecular glues show great clinical potential in treating diseases such as diabetes, cardiovascular diseases, ophthalmic disorders, and cancer. WuXi Biology has developed a comprehensive Molecular Glue Discovery Platform, equipped with DNA Encoded Library (DEL), Affinity Selection Mass Spectrometry (ASMS), and High Throughput Screening (HTS) technologies.
Animal Models of Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a chronic intestinal condition that is mediated by genetic, immune, and environmental factors. Due to its long-term, relapsing course, IBD can result in repeated cycles of mucosal damage and repair, potentially increasing the risk of colorectal cancer over time. While current treatments focus on reducing inflammation, they are less effective in addressing long-term complications such as fibrosis-related intestinal strictures.
The development of new therapeutics to treat long-term complications of IBD remains a significant unmet medical need. WuXi Biology offers a broad range of preclinical services for IBD pharmacology studies. Our platform includes IBD model selection tailored to specific targets, in-life studies, histopathological and pathological scoring, immunological analysis, and inflammatory pathway/multi-factor omics analysis.
Designing Conditions for Buchwald-Hartwig Couplings
Over the past three decades, Pd-catalyzed cross-coupling reactions have become dependable tools of organic synthesis. Among these cross-coupling reactions, C-N bond formation has a higher demand of condition optimizations due to the multiple types of amine nucleophiles, and some of these are usually challenging. In our latest article, we discuss parameter selection skills for condition optimizations in Buchwald-Hartwig reactions.
For metal catalyzed cross-couplings, WuXi AppTec’s Reaction Condition Screening Platform enhances drug development efficiency by identifying optimal reaction conditions.
Metabolic Disease Platform
Metabolic diseases are considered to arise from multiple factors (such as genetics, diet, age, and environmental factors) and often affect various organs throughout the body. No single cause is solely responsible for these disorders.
To support research in this area, WuXi AppTec offers a comprehensive platform of in vitro and in vivo services. Our capabilities include a well-established panel of validated and clinically relevant animal models as well as advanced technologies to study obesity, diabetes, hyperlipidemia, and rare metabolic diseases.
Steroid Chemistry
Due to their varied bioactivities, steroids serve as a convenient moiety to attach a large number of pharmacophores for improving physicochemical and biological properties such as increased lipid solubility, target specificity, and receptor selectivity. Steroids have also become preferred motifs for the design of novel bioconjugates with diverse biological profiles.
WuXi AppTec’s Research Chemistry Services (RCS) provides a comprehensive platform to support steroid chemistry. RCS offers custom synthesis, isotope labeling, process route development, and scale up services. Our advanced capabilities include the conjugation of steroid molecules with new modalities, such as PROTACs® and oligonucleotides.
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Covalent Chemistry Drug Discovery
With advancements in drug design, there is resurging interest in drugs that form covalent bonds with their targets, often referred to as targeted covalent inhibitors (TCIs). Covalent drugs have the potential to provide enhanced potency and prolonged duration of action compared to non-covalent drugs.
WuXi AppTec’s Research Chemistry Services (RCS) offers a comprehensive platform to support covalent chemistry. Our services include custom compound synthesis, analysis, and purification. We also provide advanced LC/MS-based capabilities to evaluate off-target binding, in-cell target occupancy, and binding site identification via peptide mapping.
NLRP3 Inhibitor Reverses Melanoma-Induced Vitiligo
Vitiligo is an autoimmune disorder characterized by the progressive destruction of melanocytes in the skin. This condition is driven by the infiltration of endogenous autoreactive CD8+ T cells, which target and destroy melanocytes, resulting in the clinical manifestation of skin depigmentation. As a common acquired skin disease with no highly effective treatments, there is an urgent need for the development of more effective therapies.
Recent studies have shown that NLRP3 inhibitors can reduce CD8+ T cell activity, highlighting NLRP3 as a potential target for treating vitiligo. At SITC 2024, WuXi AppTec presented a poster showcasing the successful establishment of an in vivo mouse model to support research in this area. The authors demonstrate that treatment with an NLRP3 inhibitor effectively reversed the symptoms of melanoma-induced vitiligo in mice.
Imiquimod-induced Psoriasis-like Dermatitis in NHP
Psoriasis is a chronic autoimmune skin disease characterized by abnormal keratinocyte proliferation and infiltration of inflammatory cells. The absence of a suitable animal model that accurately mimics the complex phenotype of psoriasis in humans has hindered the development of promising therapeutics to treat this condition.
At SITC 2024, WuXi AppTec presented a poster showcasing the use of imiquimod to induce psoriasis-like biological and pathological symptoms in NHPs, aiming to facilitate the efficacy evaluation of potential psoriasis treatments. The authors demonstrate that this NHP model can replicate key pathological features of human psoriasis, including clinical appearance, histological changes, and inflammatory cytokine profiles.
DELvision: A Protein-DEL Interaction Database
Currently, there is a lack of efficient experimental strategies to collect high-quality proteome level data for protein-ligand interactions (PLIs). At the 2024 Machine Learning Drug Discovery Symposium at the Broad Institute, WuXi AppTec presented a poster showcasing our advanced DELvision database, representing the first use of DNA-encoded library (DEL) technology for establishing a protein-DEL interaction database.
The authors demonstrate how DEL can be applied for profiling vast small molecule chemical spaces for their binding capabilities with thousands of proteins. In this manner, the DELvision database can contribute to bridging the gap between a large chemical space and the druggable genome.
OncoWuXi 3.0: New Upgrade Empowering Drug Development
The OncoWuXi database has successfully upgraded to version 3.0, marking a significant transformation! We have not only fully optimized the interface design to enhance user experience, but we have also made substantial advancements in the functionality, depth, and breadth of the database.
OncoWuXi 3.0 is committed to providing you with a comprehensive, precise, and efficient pharmacological model database platform across multiple disease domains, tailored to meet the professional needs of researchers and drug development partners.
Pancreatitis Animal Models
Pancreatitis is a condition that causes inflammation of the pancreas and is one of the most common reasons for gastrointestinal hospitalizations due to its significant incidence and potential for severe complications. Existing treatments may cause side effects such as allergies and gastrointestinal injuries, and there is an urgent need for more effective therapies.
To aid in the development of new drugs for the prevention and treatment of pancreatitis, WuXi Biology has established various acute and chronic pancreatitis models in mice. In our latest issue of OncoWuXi Express, we highlight a case study demonstrating how a caerulein-induced mouse model can effectively simulate the pathological characteristics of acute pancreatitis.