6B0F

ESTROGEN RECEPTOR ALPHA LIGAND BINDING DOMAIN IN COMPLEX WITH LSZ102

Summary for 6B0F

• Entry DOI: 10.2210/pdb6b0f/pdb
• Descriptor: Estrogen receptor, LSZ102, GLYCEROL, ... (4 entities in total)
• Functional Keywords: nuclear receptor, hormone receptor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 59012.96

Authors

Kirby, C.A.,Baird, J. (deposition date: 2017-09-14, release date: 2018-04-04, Last modification date: 2024-04-03)

Primary citation

Tria, G.S.,Abrams, T.,Baird, J.,Burks, H.E.,Firestone, B.,Gaither, L.A.,Hamann, L.G.,He, G.,Kirby, C.A.,Kim, S.,Lombardo, F.,Macchi, K.J.,McDonnell, D.P.,Mishina, Y.,Norris, J.D.,Nunez, J.,Springer, C.,Sun, Y.,Thomsen, N.M.,Wang, C.,Wang, J.,Yu, B.,Tiong-Yip, C.L.,Peukert, S.
Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.
J. Med. Chem., 61:2837-2864, 2018

PubMed 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.

PubMed: 29562737
DOI: 10.1021/acs.jmedchem.7b01682

Experimental method

X-RAY DIFFRACTION (2.86 Å)