Olema Oncology reveals NCoR1-driven ER antagonism by palazestrant and OP-3136 synergy
Palazestrant fully recruits corepressor NCoR1 to completely antagonize ERα transcription and demonstrated anti-tumor activity in wild-type and mutant ER+/HER2- models. Combining palazestrant with OP-3136 synergistically suppressed cell-cycle and ER-driven oncogenic signaling and both agents advance in clinical development—palazestrant in two Phase 3 trials and OP-3136 enrolling in Phase 1 study.
1. Preclinical Mechanism Confirmation
Palazestrant directly recruits the corepressor protein NCoR1 to fully antagonize estrogen receptor alpha, completely blocking ER-driven transcription in both wild-type and mutant ER+/HER2- breast cancer cell models and demonstrating potent in vitro anti-tumor activity without partial agonist effects.
2. Synergistic Activity in In Vivo Models
Combined administration of OP-3136, a selective KAT6 inhibitor, with palazestrant in ER+/HER2- xenograft models produced synergistic tumor growth inhibition mediated by downregulation of cell-cycle genes (MYC, E2F, G2M) and suppression of estrogen receptor-driven oncogenic and mTORC1 signaling pathways.
3. Ongoing Clinical Development
Palazestrant is currently being evaluated in two pivotal Phase 3 OPERA trials as monotherapy and in combination with ribociclib, with top-line data expected this fall, while OP-3136 has initiated patient enrollment in an ongoing Phase 1 study exploring its combination potential.