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

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.
George S Tria 1,  Tinya Abrams 1,  Jason Baird 1,  Heather E Burks 1,  Brant Firestone 1,  L Alex Gaither 1,  Lawrence G Hamann 1,  Guo He 1,  Christina A Kirby 1,  Sunkyu Kim 1,  Franco Lombardo 1,  Kaitlin J Macchi 1,  Donald P McDonnell 2,  Yuji Mishina 1,  John D Norris 2,  Jill Nunez 1,  Clayton Springer 1,  Yingchuan Sun 1,  Noel M Thomsen 1,  Chunrong Wang 1,  Jianling Wang 1,  Bing Yu 1,  Choi-Lai Tiong-Yip 1,  Stefan Peukert 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Inc. , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States.
  • 2 Department of Pharmacology and Cancer Biology , Duke University School of Medicine , Durham , North Carolina 27710 , United States.
PMID: 29562737 DOI: 10.1021/acs.jmedchem.7b01682
Abstract

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.

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