Innovative, combinatorial and high-throughput approaches to degrader synthesis

Stevens, Rebecca and Thompson, James D. F. and Fournier, Julie C. L. and Burley, Glenn A. and Battersby, David J. and Miah, Afjal H. (2024) Innovative, combinatorial and high-throughput approaches to degrader synthesis. Chemical Society Reviews, 53 (10). pp. 4838-4861. ISSN 0306-0012 (https://doi.org/10.1039/d3cs01127e)

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Abstract

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 via induced proximity. Their optimisation thus far has often been largely empirical, requiring the synthesis and screening of a large number of analogues. In addition, the synthesis and development of degraders is often challenging, leading to lengthy optimisation campaigns to deliver candidate-quality compounds. This review highlights how the synthesis of degraders has evolved in recent years, in particular focusing on means of applying high-throughput chemistry and screening approaches to expedite these timelines, which we anticipate to be valuable in shaping the future of degrader optimisation campaigns.