SLAS discovery : advancing life sciences R & D最新文献

In recent decades, the development of targeted covalent inhibitors (TCIs) has significantly advanced, as evidenced by the increasing number of FDA approved drugs with covalent mechanisms of action. This study focuses on the application of a robust and efficient screening platform to identify covalent fragments that modify the methyl-lysine reader protein M-phase phosphoprotein 8 (MPP8). Using a commercially available covalent fragment library with various electrophile-based warheads, we screened for fragments that covalently label MPP8 using matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. Follow-up validation and prioritization studies involving evaluation of the reactivity of hit fragments with glutathione led to the identification of two novel acrylamide-containing fragments that covalently label MPP8 at cysteine 99, which is adjacent to the methyl-lysine binding pocket. These results emphasize the value of efficient screening approaches in discovering novel covalent fragments for challenging targets and demonstrate the potential for developing covalent antagonists targeting MPP8.

CD28 is a pivotal costimulatory receptor involved in T cell activation and immune regulation, positioning it as a key therapeutic target for inflammatory diseases, including inflammatory bowel disease (IBD). Despite its potential, small molecules targeting CD28 are still limited. To fill this gap, we developed a high-throughput screening (HTS) platform based on Temperature-Related Intensity Change (TRIC) technology, enabling rapid, immobilization-free screening of chemical libraries of small molecules. Using the Dianthus instrument, we applied our optimized TRIC assay for CD28 (signal-to-noise ratio of 21.99) to screen two MedChemExpress libraries: Small Molecule Immuno-Oncology Compounds (SMIOC) and Protein-Protein Interaction Inhibitors (PPII), identifying 50 initial hits. Following exclusion of compounds with dye interference or aggregation artifacts, 12 candidates were prioritized for further validation. Microscale thermophoresis (MST) confirmed dose-dependent binding of seven compounds to CD28, with affinities in the micromolar range. Surface plasmon resonance (SPR) further validated two compounds, EABP 02,303 and CTEP, as CD28 binders. These results demonstrate that our TRIC-based HTS platform is robust, scalable, and effective for identifying small molecule CD28 binders. The incorporation of orthogonal validation supports the reliability of our findings and highlights the feasibility of small-molecule discovery targeting CD28.

Four years after the beginning of the COVID-19 pandemic, it is important to reflect on the events that have occurred during that time and the knowledge that has been gained. The response to the pandemic was rapid and highly resourced; it was also built upon a foundation of decades of federally funded basic and applied research. Laboratories in government, pharmaceutical, academic, and non-profit institutions all played roles in advancing pre-2020 discoveries to produce clinical treatments. This perspective provides a summary of how the development of high-throughput screening methods in a biosafety level 3 (BSL-3) environment at Southern Research Institute (SR) contributed to pandemic response efforts. The challenges encountered are described, including those of a technical nature as well as those of working under the pressures of an unpredictable virus and pandemic.