The Chemical Biology group at Merck aims to provide novel, high-quality targets and expand confidence on molecular mechanism of action of key assets. As part of our efforts to connect novel mechanisms to high value, translatable targets, we leverage phenotypic screening to identify promising targets to treat inflammation, cancer, and neurodegeneration, and other diseases.

The work presented today will briefly cover our efforts in leveraging differences in macrophage polarization and the mechanisms and targets that modulate it. To circumvent the limitations of conventional screening methods we combined morphological profiling by Cell Painting with machine learning to create a novel high-throughput phenotypic screening workflow.

Using our screening platform, we evaluated a small molecule library containing 1579 compounds with known mechanisms of action and 3840 compounds selected for chemical diversity for their ability to modulate macrophage polarization. CRISPR-Cas9 knockout screening approaches comprised of 9300 genes were applied to complement the small molecule screen and capture a wider variety of genes representing multiple cellular functions. This work demonstrates that morphological profiling can be applied to primary human cells to identify novel small molecules and genetic targets for the modulation of macrophage polarization.