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

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

来源：Journal of Medicinal Chemistry, 2018, 61(7): 2837-2864.

DOI：10.1021/acs.jmedchem.7b01682

In breast cancer, estrogen receptor alpha (ER alpha) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERa 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 ER alpha positive breast cancer.

• 出版日期2018-4-12