Breast cancer is the second leading cause of cancer death in women. Approximately 70% breast cancers are ER-positive. Despite the initial effectiveness of standard of care therapies, 20-30% of patients eventually relapse and become resistant. Among the recently discovered clinical candidates, GDC-0927 is a full ERα antagonist in breast and uterine tissues and is highly efficacious in tamoxifen-sensitive and -resistant xenograft models. However, GDC-0927 suffers from low oral exposure as a result of high clearance and low oral bioavailability. This is likely due to the presence of two electron-rich phenols in the molecule. The structural modifications identified several metabolically stable analogs, however, at the expense of potency. Subsequently, our crystal structure of GDC-0927 guided the design of a novel C8-hydroxy chromene in which the neighboring oxygen atom of the chromene was envisioned to shield the hydroxyl group from glucuronide conjugation and thereby improve clearance. Gratifyingly, this analog exhibited excellent enzyme potency and degradation efficiency with improved oral exposure in rat compared to GDC-0927.  These efforts, the crystal structures of GDC-0927 and the novel C8-hydroxy chromene will be discussed.

Discovery of a C-8 hydroxychromene as a potent inhibitor of estrogen receptor alpha with improved rat oral exposure over GDC-0927

2019 Fall National Meeting

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