Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer

Androgen Receptor (AR) signaling plays a pivotal role in the development and progression of prostate cancer. Herein, we describe the discovery and optimization of a novel series of AR PROTACs capable of degrading AR and important resistance mutations such as L702H AR. A novel AR-binding cyanoindole motif was identified from a directed screen of the AstraZeneca collection. This was optimized and elaborated to identify a suitable exit vector from which to form an initial PROTAC capable of degrading AR. The series was further optimized in terms of potency and rodent oral bioavailability with an isomeric switch of the piperidine substitution, removing an <i>in vitro</i> mitotoxicity signal to give <b>3n</b>. This compound inhibited AR signaling <i>in vitro</i> and was able to inhibit tumor growth <i>in vivo</i> in a mouse prostate cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-01-30
DOI
https://doi.org/10.1021/acs.jmedchem.5c03138
Primary Topic
Protein Degradation and Inhibitors
Type
article
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article

Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer

Stuart E. Pearson, Gary Fairley, Erin Braybrooke, Oliver Steward et al.
Journal of Medicinal Chemistry
Protein Degradation and Inhibitors
article

Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer

Stuart E. Pearson, Gary Fairley, Erin Braybrooke, Oliver Steward, Doyle J. Cassar, James S. Scott, Monica C. Rodrigo-Brenni, Sharan K. Bagal, Terence M. Jones, Michael Niedbala, Antonio Ramos‐Montoya, Charlene Fallan, Thomas Hammond, Martin J. Packer, Claire Crafter, Laura Evans, Núria Galeano-Dalmau, J.C. Komen, Argyrides Argyrou, Ziyanda Shologu, Joseph Shaw, Peter C. Astles, Andy Pike, Markus Schade, Chrysiis Michaloglou, Gillian M. Lamont, Andreas K. Hock, David Beattie, Coura Diène, Graham Fraser
article en

Abstract

Androgen Receptor (AR) signaling plays a pivotal role in the development and progression of prostate cancer. Herein, we describe the discovery and optimization of a novel series of AR PROTACs capable of degrading AR and important resistance mutations such as L702H AR. A novel AR-binding cyanoindole motif was identified from a directed screen of the AstraZeneca collection. This was optimized and elaborated to identify a suitable exit vector from which to form an initial PROTAC capable of degrading AR. The series was further optimized in terms of potency and rodent oral bioavailability with an isomeric switch of the piperidine substitution, removing an <i>in vitro</i> mitotoxicity signal to give <b>3n</b>. This compound inhibited AR signaling <i>in vitro</i> and was able to inhibit tumor growth <i>in vivo</i> in a mouse prostate cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750.

Journal of Medicinal ChemistryVol. 69(3)
AstraZeneca (South Korea) (KR), AstraZeneca (Singapore) (SG), AstraZeneca (Brazil) (BR)
Good health and well-being
Openalex Percentile: Top 72%
Protein Degradation and Inhibitors
DOISourceOpenAlex
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