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

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journal contribution
posted on 29.11.2016, 00:00 by Jiawang Liu, Shilong Zheng, Shanchun Guo, Changde Zhang, Qiu Zhong, Qiang Zhang, Peng Ma, Elena V. Skripnikova, Melyssa R. Bratton, Thomas E. Wiese, Guangdi Wang
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.