2. Academic Validation
  3. Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer

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

  • J Med Chem. 2026 Feb 12;69(3):3209-3232. doi: 10.1021/acs.jmedchem.5c03138.
James S Scott 1,  Laura Evans 1,  Peter C Astles 1,  Argyrides Argyrou 2,  Sharan K Bagal 1,  David Beattie 1,  Erin L Braybrooke 1,  Doyle J Cassar 1,  Claire Crafter 1,  Coura Diène 1,  Gary Fairley 3,  Charlene Fallan 1,  Graham Fraser 1,  Nuria Galeano-Dalmau 1,  Thomas G Hammond 4,  Andreas K Hock 2,  Thomas Jones 2,  Jasper Komen 4,  Gillian M Lamont 1,  Chrysiis Michaloglou 1,  Michael J Niedbala 5,  Antonio Ramos-Montoya 1,  Monica C Rodrigo-Brenni 4,  Martin J Packer 3,  Stuart Pearson 1,  Andy Pike 1,  Markus Schade 1,  Joseph Shaw 2,  Ziyanda Shologu 1,  Oliver Steward 1
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2 Discovery Sciences, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 3 Oncology R&D, AstraZeneca, Macclesfield SK10 2NA, U.K.
  • 4 Safety Sciences, Clinical Pharmacology and Safety Sciences, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 5 Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
PMID: 41612563 DOI: 10.1021/acs.jmedchem.5c03138
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 in vitro mitotoxicity signal to give 3n. This compound inhibited AR signaling in vitro and was able to inhibit tumor growth in vivo in a mouse prostate Cancer xenograft model. Extensive profiling in terms of drug-like properties allowed this to be progressed into development as AZD9750.

Figures
Products