2. Academic Validation
  3. Discovery of a Series of Orally Bioavailable Androgen Receptor Degraders for the Treatment of Prostate Cancer

Discovery of a Series of Orally Bioavailable Androgen Receptor Degraders for the Treatment of Prostate Cancer

  • J Med Chem. 2024 Jul 25;67(14):11732-11750. doi: 10.1021/acs.jmedchem.4c00269.
Sharan K Bagal 1,  Peter C Astles 1,  Coura Diène 1,  Argyrides Argyrou 2,  Claire Crafter 1,  Doyle J Cassar 1,  Charlene Fallan 1,  Andreas Hock 2,  Thomas Jones 2,  Kevin Moreau 3,  Gillian M Lamont 1,  Scott Lamont 1,  Chrysiis Michaloglou 1,  Martin J Packer 1,  Andy Pike 1,  Antonio Ramos-Montoya 1,  James S Scott 1,  Joseph Shaw 2,  Ziyanda Shologu 1
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 2 Discovery Sciences R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 3 Clinical Pharmacology and Safety Sciences, AstraZeneca, Cambridge CB4 0WG, U.K.
PMID: 38991141 DOI: 10.1021/acs.jmedchem.4c00269
Abstract

Androgen Receptor (AR) signaling plays a key role in the progression of prostate Cancer. This study describes the discovery and optimization of a novel series of AR PROTAC degraders that recruit the Cereblon (CRBN) E3 Ligase. Having identified a series of AR ligands based on 4-(4-phenyl-1-piperidyl)-2-(trifluoromethyl)benzonitrile, our PROTAC optimization strategy focused on linker connectivity and CRBN ligand SAR to deliver potent degradation of AR in LNCaP cells. This work culminated in compounds 11 and 16 which demonstrated good rodent oral bioavailability. Subsequent SAR around the AR binding region brought in an additional desirable feature, degradation of the important treatment resistance mutation L702H. Compound 22 (AZ'3137) possessed an attractive profile showing degradation of AR and L702H mutant AR with good oral bioavailability across species. The compound also inhibited AR signaling in vitro and tumor growth in vivo in a mouse prostate Cancer xenograft model.

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