Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation.

High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis and biological evaluation of crude mixtures in cellular assays. The rise of these workflows has rapidly accelerated drug-discovery programs in the field of targeted protein degradation (TPD) in recent years by removing a key bottleneck of compound purification. However, the number of chemical transformations amenable to this methodology remain minimal, leading to limitations in the exploration of chemical space using existing library-based approaches.

Innovative, combinatorial and high-throughput approaches to degrader synthesis.

Targeted protein degraders such as PROTACs and molecular glues are a rapidly emerging therapeutic modality within industry and academia. Degraders possess unique mechanisms of action that lead to the removal of specific proteins by co-opting the cell's natural degradation mechanisms induced proximity. Their optimisation thus far has often been largely empirical, requiring the synthesis and screening of a large number of analogues.

Integrated Direct-to-Biology Platform for the Nanoscale Synthesis and Biological Evaluation of PROTACs.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that co-opt the cell's natural proteasomal degradation mechanisms to degrade undesired proteins. A challenge associated with PROTACs is the time and resource-intensive optimization; thus, the development of high-throughput platforms for their synthesis and biological evaluation is required. In this study, we establish an ultra-high-throughput experimentation (ultraHTE) platform for PROTAC synthesis, followed by direct addition of the crude reaction mixtures to cellular degradation assays without any purification.

Synthesis of Arylethylamines C(sp)-C(sp) Palladium-Catalyzed Cross-Coupling.

Substituted arylethylamines represent a key structural motif in natural, pharmaceutical, and agrochemical compounds. Access to such scaffolds has been the subject of long-standing synthetic interest. Herein, we report the synthesis of such scaffolds a palladium-catalyzed C(sp)-C(sp) coupling between (chloromethyl)aryls and air-/moisture-stable ,-dialkylaminomethyltrifluoroborate salts.