Discovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer

Selective estrogen receptor degraders (SERDs) deplete
the ER signaling
pathway via antagonism and degradation of ERα and represent
a promising strategy to tackle endocrine resistance. Here, we report
a new class of SERDs by pharmacological evolution of a selective estrogen
receptor modulator, lasofoxifene. The structure–activity relationship
study and efforts to circumvent the issue of human ether-a-go-go-related
gene led to the identification of compounds 51. This
bifunctional compound displayed broad activity across a vast array
of cell backgrounds and was capable of effectively degrading and antagonizing
wild-type ERα and clinically relevant ERα mutants. 51 exhibited favorable pharmacokinetic properties and good
brain penetration, with a brain/plasma ratio of 3.05, and significantly
suppressed the growth of tumor in a tamoxifen-resistant MCF-7 Tam1
xenograft model. Overall, the study demonstrates 51 as
a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a
good potential in overcoming endocrine resistance.