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 . 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. 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 as a highly potent, oral, and brain penetrant ER degrader and pure antagonist, showing a good potential in overcoming endocrine resistance.