title: Rational Design of a Boron-Modified Triphenylethylene (GLL398) as an Oral Selective Estrogen Receptor Downregulator.
abstract: 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. Compound9strongly 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 of9(AUC = 36.9 μg·h/mL) in rats as compared to GW7604 (AUC = 3.35 μg·h/mL). The strikingly favorable pharmacokinetic property of9makes it a promising oral SERD suitable for clinical evaluation.
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Shilong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Shanchun
authors.initials: S
authors.lastname: Guo
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Changde
authors.initials: C
authors.lastname: Zhang
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Ma
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Skripnikova
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Melyssa R
authors.initials: MR
authors.lastname: Bratton
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wiese
authors.affiliation: RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
keywords: Hormonal therapy; boronic acid; oral bioavailability; pseudo-SERD; selective estrogen receptor downregulator (SERD)