Profiling cells with DELs: Small molecule fingerprinting of cell surfaces

•We demonstrate distinct binding profiles for small molecule ligands from DNA encoded libraries (DELs) affinity selected to various mouse and human cell types.•Specific exemplar molecules are identified and shown to bind mouse myotube cells over myoblasts, and human Molt4 cells over Ramos, Raji, Daudi, and K562 cells.•These results support the use of DELs alongside other affinity binding technologies to profile cell states and identify biomarkers and therapeutic targets. DNA-encoded small molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, it has been used to identify ligands against targets that are soluble or overexpressed on cell surfaces. Here, we report applying cell-based selection methods to profile surfaces of mouse C2C12 myoblasts and myotube cells in an unbiased, target agnostic manner. A panel of on-DNA compounds were identified and confirmed for cell binding selectivity. We optimized the cell selection protocol and employed a novel data analysis method to identify cell selective ligands against a panel of human B and T lymphocytes. We discuss the generality of using this workflow for DNA encoded small molecule library selection and data analysis against different cell types, and the feasibility of applying this method to profile cell surfaces for biomarker and target identification. [Display omitted]