PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an increasingly powerful new therapeutic modality in drug discovery. Selective degradation of target proteins is enabled by the heterodimeric structure of PROTACs, consisting of 2 small molecule ligands connected covalently by a linker. This allows simultaneous binding to the protein of interest (POI) and to an E3 ubiquitin ligase, triggering the degradation cascade. However, exploration of complex structure-activity relationships (SAR) for PROTACs typically require multi-step and resource-intensive synthetic campaigns which pose a significant limit to the discovery of new degraders. To address this currently unmet challenge, late-stage C-H functionalization was envisaged as an attractive approach to provide rapid and modular access to PROTACs from advanced drug molecules.<br/>This presentation will describe the development of a ruthenium-catalyzed C-H amidation protocol for the late-stage synthesis of PROTACs. Using readily available dioxazolone reagents, several inherent functional groups can successfully guide the C–H activation in a predictable manner. High chemoselectivity and functional group tolerance allows the conjugation of a broad range of linkers and POI ligands. Finally, application of the methodology to the single-step synthesis of PROTACs and other drug conjugates, without need for pre-functionalization or post-deprotection, is demonstrated.

Single-step access to PROTACs via late-stage C-H amidation

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