Rational Design of a Boron-Modified Triphenylethylene (GLL398) as an Oral Selective Estrogen Receptor Downregulator

Development of orally bioavailable nonsteroidal selective Estrogen Receptor downregulators (SERDs) provides clinical opportunities for the long-term treatment and Adjuvant therapy of breast Cancer at all stages. We describe the design, synthesis, and identification of a boron-modified GW7604 derivative (GLL398, 9), a SERD candidate, in which a boronic acid functional group replaces the phenolic hydroxyl group of GW7604. Compound 9 strongly binds to ERα in a fluorescence resonance energy transfer binding assay (IC₅₀ = 1.14 nM) and potently degrades ERα in MCF-7 breast Cancer cells (IC₅₀ = 0.21 μM). Most importantly, the introduction of the boronic acid group confers superior oral bioavailability of 9 (AUC = 36.9 μg·h/mL) in rats as compared to GW7604 (AUC = 3.35 μg·h/mL). The strikingly favorable pharmacokinetic property of 9 makes it a promising oral SERD suitable for clinical evaluation.

Hormonal therapy; boronic acid; oral bioavailability; pseudo-SERD; selective estrogen receptor downregulator (SERD).