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

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Stevens, Rebecca and Shrives, Harry J. and Cryan, Jenni and Klimaszewska, Diana and Stacey, Peter and Burley, Glenn A. and Harling, John D. and Battersby, David J. and Miah, Afjal H. (2024) Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation. RSC Medicinal Chemistry. ISSN 2632-8682 (https://doi.org/10.1039/D4MD00760C)

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Abstract

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. In this work, we expanded the toolbox by synthesising a library of degraders in D2B format. First, reaction conditions are established for performing key medicinal chemistry transformations, including reductive amination, SNAr, palladium-mediated cross-coupling and alkylation, in D2B format. Second, the utility of these alternative reactions is demonstrated by rapidly identifying developable PROTACs for a range of protein targets.

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