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, <i>ESR1</i>, that constitutively activate the estrogen receptor leads to relapse. Complete antagonism of both WT and mutant <i>ESR1</i> (<i>mutESR1</i>) 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 <i>mutESR1</i> 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).
Authors
- Judevin Sapugay (ORCID: https://orcid.org/0000-0001-7493-2490)
- Guijun Yu
- Geoffrey L. Greene (ORCID: https://orcid.org/0000-0001-6894-8728)
- Peter J. Kushner (ORCID: https://orcid.org/0009-0005-2680-6912)
- Brian R. Hearn (ORCID: https://orcid.org/0000-0002-2078-5728)
- Susan L. Andersen
- Guadalupe Peña (ORCID: https://orcid.org/0000-0003-2500-2478)
- Brian Rich
- David C. Myles (ORCID: https://orcid.org/0009-0003-9074-2349)
- Samiron Phukan (ORCID: https://orcid.org/0000-0002-5009-2340)
- Richard Sun (ORCID: https://orcid.org/0009-0001-6702-1442)
- Sean William Fanning (ORCID: https://orcid.org/0000-0002-9428-0060)
- Raymond Ng (ORCID: https://orcid.org/0000-0002-2815-7718)
- Srinivasan Thangathirupathy
- Dirk A. Heerding
- Alison D. Parisian (ORCID: https://orcid.org/0000-0001-5706-0571)
- Susanna A. Barratt (ORCID: https://orcid.org/0000-0001-6303-787X)
- Cyrus L. Harmon (ORCID: https://orcid.org/0009-0007-5428-0617)
- Donald R. Zak (ORCID: https://orcid.org/0000-0002-9730-7337)
- Gopinath S. Palanisamy (ORCID: https://orcid.org/0009-0002-4904-316X)
- Leslie Hodges-Gallagher (ORCID: https://orcid.org/0009-0005-9425-8380)
- Tsuyoshi Watanabe (ORCID: https://orcid.org/0000-0002-6094-7728)
- Brandon Robello (ORCID: https://orcid.org/0009-0007-7726-7538)
- Chenbo Wang (ORCID: https://orcid.org/0000-0002-1423-0726)
- Fei Zhou (ORCID: https://orcid.org/0000-0001-6122-5471)
- Alison Duncan
- Reena Chawla
- David Yeghikyan
- Samir Satish Kher
- Robert Millikin
Institutions
- Union University (US)
- Loyola University Chicago (US)
- Genesis HealthCare (US)
- University of Chicago (US)
- May Institute (US)
- Syntermed (United States) (US)
- Sugen Life Sciences (India) (IN)
- Genesis Research Institute (JP)
- Delaware Department of Health and Social Services (US)
- Olema Pharmaceuticals (United States) (US)
Publication Details
- Journal
- ACS Omega
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1021/acsomega.4c11023
- Citations
- 1
- Primary Topic
- Estrogen and related hormone effects
- Type
- article
- Field-Weighted Citation Impact
- 1.82