Selection of DNA-encoded chemical libraries (DELs) against cancer cells without predefined targets

Abstract

DNA-encoded chemical library technology is emerging as an immensely powerful interrogation modality for hit generation in drug discovery. Albeit recent embodiments elaborate the capability of conventional DELs to conduct in the complex milieu of biological systems, however, the applications of DELs have been predominantly limited to beforehand designated targets. The selection against multiple targets, without a designated one, remains a challenge. Herein, we report a straightforward method, capable of profiling the intact cells unbiasedly, regardless prior knowledge of target molecules, to generate recognition ligands specifically to cell type of interest. We demonstrate the generality and utility of this approach by screening large scale DNA3 encoded chemical library against a panel of highly metastatic and low-metastatic breast cancer cells, and yield the discovery of clusters of probes and individual ligand for the specific recognition of aggressive MDA-MB-231 cells, with double-to- single-digit micromolar ligands binding affinity. This study highlights opportunities for the possibility to investigate multiplexed targets by harnessing the power of DEL in their native environment, possible paving the way to individualized cancer treatment in the future.