Abstract A107: Small Molecule Degraders of the Estrogen Receptor (SERDs): Optimization of the tricyclic indole scaffold beyond AZD9496

The estrogen receptor alpha (ERα) is expressed in >70% of breast cancers and is a clinically validated target in oncology.1 Anti-hormonal therapies that directly block ER function (e.g., tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances have been made with the development of SERDs (Selective Estrogen Receptor Degraders) such as fulvestrant which both antagonise ERα-driven tumor cell growth and cause degradation of the ERα receptor.2 We previously disclosed the identification of a tricyclic indole scaffold that led to the orally active clinical candidate AZD9496.3 Additional work to identify novel chemotypes including phenol 14 and indazole 25 was also disclosed together. The work previously disclosed relied on the presence of the acrylic acid for efficient degradation of the estrogen receptor. In this poster we will discuss the replacement of the acrylic acid on the tricyclic indole scaffold with amines (e.g. compound 3). Compound 3 is a degrader of the estrogen receptor in the MCF-7 cell line (pIC50 8.4). Further optimisation of lead structure 3 led to more potent selective degraders of the estrogen receptor in multiple cell lines (e.g. pIC50 >10 in MCF-7) with suitable properties for oral absorption (e.g. oral AUC 44 μM.h in mice at 20 mg/kg). We will discuss some of the medicinal chemistry challenges that were faced along the way and the optimisation strategy (use of NMR derived solution phase conformations, understanding of the binding mode in the estrogen receptor by X-ray crystallography). ol> Citation Format: Bernard Barlaam, Jason Breed, Rodrigo J Carbajo, Eric Gangl, Samantha Hughes, Christopher J Morrow, Thomas A Moss, Radoslaw Polanski, Willem M Nissink, Daniel O9Donovan, Jeffrey Varnes, Bin Yang, James S Scott. Small Molecule Degraders of the Estrogen Receptor (SERDs): Optimization of the tricyclic indole scaffold beyond AZD9496 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A107. doi:10.1158/1535-7163.TARG-19-A107