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

Journal: ACS medicinal chemistry letters
Published Date: Nov 29, 2016

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, ), a SERD candidate, in which a boronic acid functional group replaces the phenolic hydroxyl group of GW7604. Compound strongly binds to ERα in a fluorescence resonance energy transfer binding assay (IC = 1.14 nM) and potently degrades ERα in MCF-7 breast cancer cells (IC = 0.21 μM). Most importantly, the introduction of the boronic acid group confers superior oral bioavailability of (AUC = 36.9 μg·h/mL) in rats as compared to GW7604 (AUC = 3.35 μg·h/mL). The strikingly favorable pharmacokinetic property of makes it a promising oral SERD suitable for clinical evaluation.

Authors

  • Jiawang Liu
    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.
  • Shilong Zheng
    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.
  • Shanchun Guo
    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.
  • Changde Zhang
    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.
  • Qiu Zhong
    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.
  • Qiang Zhang
    Yunan Provincial Center for Disease Control and Prevention, Kunming 650022, China.
  • Peng Ma
    RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
  • Elena V Skripnikova
    RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
  • Melyssa R Bratton
    RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
  • Thomas E Wiese
    RCMI Cancer Research Center and College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
  • Guangdi Wang
    Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.

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