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

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.