8VV1

Estrogen receptor alpha ligand binding domain in complex with palazestrant

This is a non-PDB format compatible entry.

Summary for 8VV1

• Entry DOI: 10.2210/pdb8vv1/pdb
• Descriptor: Estrogen receptor, palazestrant, GLYCEROL, ... (4 entities in total)
• Functional Keywords: estrogen receptor, ceran, ligand binding domain, alpha helical bundle, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 57701.71

Authors

Ng, R.A.,Barratt, S.,Parisian, A.,Palanisamy, G.,Sun, R.,Robello, B.,Pena, G.,Sapugay, J.,Yeghikyan, D.,Duncan, A.,Andersen, S.E.,Chawla, R.,Rich, B.,Hearn, B.,Harmon, C.,Hodges-Gallagher, L.,Kushner, P.J.,Greene, G.L.,Myles, D.C.,Fanning, S.W. (deposition date: 2024-01-30, release date: 2025-03-19, Last modification date: 2026-04-01)

Primary citation

Ng, R.A.,Barratt, S.,Parisian, A.,Palanisamy, G.S.,Phukan, S.,Sun, R.,Robello, B.,Pena, G.,Sapugay, J.,Yeghikyan, D.,Wang, C.,Satish Kher, S.,Thangathirupathy, S.,Millikin, R.,Yu, G.,Watanabe, T.,Zhou, F.,Rich, B.,Duncan, A.,Andersen, S.E.,Chawla, R.,Zak, D.R.,Heerding, D.A.,Hearn, B.R.,Greene, G.,Harmon, C.L.,Hodges-Gallagher, L.,Kushner, P.J.,Fanning, S.W.,Myles, D.C.
Discovery of Palazestrant (OP-1250), a Potent and Orally Bioavailable Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD).
Acs Omega, 10:22685-22700, 2025

PubMed Abstract: 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, , that constitutively activate the estrogen receptor leads to relapse. Complete antagonism of both WT and mutant () 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 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).

PubMed: 40521471
DOI: 10.1021/acsomega.4c11023

Experimental method

X-RAY DIFFRACTION (2.196 Å)