“In the past, thousands of proteins were considered undruggable. This meant that previous efforts to develop a drug against them failed. Today, the combination of novel chemical modalities and advanced technical approaches has resulted in new clinical candidates for previously undruggable targets.”
Nuska Tschammer, Senior Manager Scientific & Technological Leadership at CRELUX, a WuXi AppTec company
Definition: A method to assess the binding of the compound to soluble protein target.
Screened Molecules: ~300K.
Definition: In DEL, compounds are individually coupled to DNA tags, which are used as amplifiable identification barcodes.
Screened Molecules: 80B+.
Definition: A method for the identification of active compounds or biologics that modulate a particular biomolecular pathway.
Screened Molecules: ~300K.
Only compounds with a strong affinity (< 10 μM) are identified
Problems screening more difficult targets, such as protein-protein interactions
Definition: A technology for detecting the movement of fluorescent molecules in temperature gradients.
Screened Molecules: 3,5K+.
Requires fluorophore labeling
Requires strong intrinsic fluorescence of the target
Definition: Ligand-observed NMR confirms ligand binding to unlabeled protein Protein-observed NMR monitors changes in the protein signal upon ligand binding.
Screened Molecules: ~1,5K
Unlabeled ligand & protein in every experiment
Requires large amounts of isotopically labeled protein
Large library screening is challenging
Definition: An optical biosensor that measures the interactions between immobilized molecules and molecules in solution.
Screened Molecules: 3,5K+
Immobilization can cause inactivation of low-stability proteins
Signal may be affected by the solvent effect
Definition: A computational method to screen in silico collections of compound libraries to identify the binders for a given target.
Screened Molecules: ~200M
Saves time compared to HTS
Requires structural information on the target or its homologs
Access to compounds is not always possible
Definition: A method that uses the fragments’ crystal structure to determine its binding mode.
Screened Molecules: ~1K
Fine mapping of fragment binding site
Requires large quantities of homogeneous protein
No affinity information
STimulator of INterferon Genes or STING plays a crucial role in the innate immune system and was long perceived as a difficult and almost undruggable target.
In 2010, for instance, a Phase III clinical trial testing the promising STING-targeting compound DMXAA flatlined. It turned out that DMXAA targeted only mouse STING protein and could not activate human STING, a crucial factor that had been overlooked from the preclinical phase through Phase II.
As a pattern recognition receptor, STING plays a part in the body’s response to pathogens, tumors, and DNA in the cytoplasm. When activated, STING triggers the production of Type I interferons and pro-inflammatory cytokines, which can be used in the fight against cancer.
MST and SPR were chosen due to their high sensitivity, low protein consumption, and short turnaround time. The hits were identified and confirmed within three weeks.
The screening methods employed helped the WuXi team at CRELUX to understand the key interactions between the fragments and the protein.
Fragment screens are well suited for gaining knowledge on the druggability of a particular target or binding site. Therefore, the high fragment hit rate determined by the WuXi team is a promising starting point for the development of a high-affinity, small-molecule ligand.
Furthermore, the team identified novel scaffolds among the fragments, which will now undergo a first round of in silico growing. The process will be followed by hit-to-lead optimization and take place within the WuXi AppTec units.
WuXi AppTec, Journal of Chemistry & Biology, FEBS Letters, Progress in Biophysics and Molecular Biology, Journal of Biomolecular Screening, The International Journal of Student Research, Journal of The American Society for Mass Spectrometry, Bioinformation, ACS Medicinal Chemistry Letters, Cell Chemical Biology, Small Molecule Targets In Immuno-Oncology
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Text: Larissa Warneck
Design and images: Elena Resko
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