Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer

J Med Chem. 2018 Apr 12;61(7):2837-2864. doi: 10.1021/acs.jmedchem.7b01682. Epub 2018 Mar 22.


In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Biological Availability
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Drug Design
  • Drug Discovery
  • Estrogen Receptor alpha / drug effects*
  • Female
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Selective Estrogen Receptor Modulators / chemical synthesis*
  • Selective Estrogen Receptor Modulators / pharmacokinetics
  • Selective Estrogen Receptor Modulators / pharmacology*
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacokinetics
  • Thiophenes / pharmacology*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Estrogen Receptor alpha
  • Selective Estrogen Receptor Modulators
  • Thiophenes
  • LSZ102