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The encoding of chemical compounds with amplifiable DNA tags facilitates the discovery of small-molecule ligands for proteins. To investigate the impact of stereo- and regiochemistry on ligand discovery, we synthesized a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids. The library was selected against multiple proteins and yielded specific ligands. The selection fingerprints obtained for a set of protein targets of pharmaceutical relevance clearly showed the preferential enrichment of ortho-, meta- or para-regioisomers, which was experimentally verified by affinity measurements in the absence of DNA. The discovered ligands included novel selective enzyme inhibitors and binders to tumour-associated antigens, which enabled conditional chimeric antigen receptor T-cell activation and tumour targeting.A DNA-encoded chemical library based on regio- and stereoisomers of phenylalanine has been synthesized and used for affinity-based selections against multiple target proteins. This approach led to the isolation and validation of potent ligands capable of CAR T-cell activation and tumour targeting.

A versatile and Lipinski‐compliant DNA‐encoded library (DEL), comprising 366 600 glutamic acid derivatives coupled to oligonucleotides serving as amplifiable identification barcodes is designed, constructed, and characterized. The GB‐DEL library, constructed in single‐stranded DNA format, allows de novo identification of specific binders against several pharmaceutically relevant proteins. Moreover, hybridization of the single‐stranded DEL with a set of known protein ligands of low to medium affinity coupled to a complementary DNA strand results in self‐assembled selectable chemical structures, leading to the identification of affinity‐matured compounds. A single‐stranded DNA‐encoded chemical library (DEL) of 366 600 compounds, based on a stereoisomeric scaffold and on a single‐stranded DNA format, allows the isolation of ligands against multiple protein targets. The library can also be hybridized to a complementary DNA strand equipped with a protein binder, in order to generate affinity‐matured ligands.

This work explores medicinal chemistry-based approaches to develop CREBBP bromodomain ligands, using protein-ligand X-ray crystallography to enable structure-guided drug design. Here, we report the improvement of affinity and selectivity for a previously reported CREBBP bromodomain inhibitor through; (i) bioisosteric modifications to remove unfavourable enthalpic contributions to binding; and (ii) macrocyclic drug design to favour the CREBBP bromodomain binding mode. These improved ligands were also incorporated into (iii) PROTACs to develop full-length CREBBP degraders as a proof-of-concept for this target. In collaboration with Prof. Dario Neri’s group (ETH Zurich), we use (iv) DNA-encoded chemical library technology to identify novel CREBBP bromodomain fragments and scaffolds. This work has provided valuable insight in the development of selective inhibitors for the CREBBP bromodomain and sets the foundations for applying new technologies to identify novel inhibitors and degraders for this target protein.