The estrogen receptor alpha (ERα) is expressed in &gt;70% of breast cancers and is a clinically validated target in oncology. 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. This presentation will describe work carried out at AstraZeneca to discover novel, orally bioavailable SERDs across a range of chemotypes. The challenges of working on phenol containing chemotypes will be discussed, together with the identification of a tricyclic indole scaffold that led to the clinical candidate AZD9496. Additional work to identify novel chemotypes including phenol 1 and indazole 2 will be described together with some of the medicinal chemistry challenges that were faced along the way. The use of NMR derived solution phase conformations as part of an optimisation strategy will also be discussed.

Small-molecule estrogen receptor degraders (SERDs): Chemical exploration and optimisation at AstraZeneca

2019 Fall National Meeting

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