Discovery of Palazestrant (OP-1250), a Potent and Orally Bioavailable Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD).

Metastatic breast cancer (mBC) is a leading cause of cancer death in women. Most breast cancer patients are administered estrogen-receptor-targeted endocrine therapies to treat or prevent progressive metastatic disease. Development of endocrine resistance through acquisition of mutations in the estrogen receptor gene, ESR1, that constitutively activate the estrogen receptor leads to relapse. Complete antagonism of both WT and mutant ESR1 (mutESR1) with an oral therapeutic that persistently antagonizes ER-driven oncogenic transcriptional activities is a requirement for efficacy. Here, we describe our discovery of the investigational drug OP-1250 (palazestrant). OP-1250 is a potent complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that is active in both WT and mutESR1 breast cancer tumors. OP-1250's effective induction of tumor regression either as a single agent or in combination with a CDK4/6 inhibitor has led to the rapid advancement of this compound into a Phase 3 clinical trial (OPERA-01).