Abstract Background: Anti-estrogen therapies and CDK4/6 inhibitors (CDK4/6i) represent the backbone 1st line treatment for patients with ER+/HER2- metastatic breast cancer (MBC). However, patients ultimately progress on therapy due to heterogenous resistance mechanisms. Activating mutations in the estrogen receptor (ER) ligand-binding domain account for ∼40-50% of this resistance. In this case, ER either fully (ER driven) or partially (ER co-driven) drives the disease. Next-generation therapies such as SERDs, PROTACs, and CERANs that degrade and/or antagonize ER are clinically active in the ER mutant setting but have weak or no activity in the ER wild-type (WT) setting where other heterogenous, non-ER mechanisms drive the disease (ER independent). Thus, there remains a significant unmet need to target ER co-driven and ER independent MBC. Regulated Induced Proximity Targeting Chimera (RIPTAC™) therapeutics are hetero-bifunctional small molecules that simultaneously bind a tumor-specific target protein (TP) and a pan-essential protein (EP). The TP:RIPTAC:EP ternary complex leads to selective inactivation of the EP only in target-containing cells. Breast cancer RIPTACs take advantage of ER expression to selectively inactivate BRD4 to induce breast cancer cell death. RIPTACs demonstrate potent cellular activity through BRD4 inactivation, regardless of ER driver status, and are expected to have broad activity across early- and late-line MBC. Methods: RIPTACs were tested for their ability to form a ternary complex between ER and BRD4. In vitro, pharmacodynamic response was assayed via qRT-PCR, and anti-proliferative activity in engineered and endogenous breast cancer cell lines was assessed. In vivo pharmacokinetic/pharmacodynamic analysis and tumor growth inhibition were assessed in both cell-line derived xenografts (CDXs) and patient-derived xenografts (PDXs). Agonist activity was assessed in the Ishikawa endometrial cell line in vitro and in juvenile rats in vivo. Results: RIPTACs form potent ternary complexes in vitro between BRD4 and both WT and multiple mutant forms of ER. Additionally, BRD4 pharmacodynamic response is observed only in ER-containing cells, resulting in nanomolar anti-proliferative activity in endocrine sensitive cell lines. RIPTACs cause significant tumor growth inhibition or regression in the endocrine sensitive MCF7 CDX model and in the ST941HI/PBR PDX model harboring ER Y537S. RIPTACs retain significant in vitro anti-proliferative activity in cell line models of post-CDK4/6i late-line resistance. Furthermore, breast cancer RIPTACs lack endometrial/uterine agonist activity, highlighting the modality’s therapeutic index and supporting the potential for clinical development across lines of BC treatment. Conclusions: These data demonstrate that RIPTACs are active across ER WT and ER mutant settings with a broad therapeutic index, thus providing an important potential treatment for patients with MBC. An ER-BRD4 RIPTAC is currently in IND-enabling studies with a Phase 1 FIH anticipated to start in 1H-2026. Citation Format: D. E. Puleo, M. A. Perry, M. B. Martin, C. D. Forbes, K. M. Jones, A. McGovern, A. Hundt, S. Fasciano, R. Stronk, M. P. King, A. Ward, K. Cooney-Walsh, K. Howard, C. Marshall, E. Attar, K. J. Eastman, K. Raina, K. J. Kayser-Bricker. Er riptacs drive tumor selective cell death in post-cdk4/6i resistance settings and demonstrate oral efficacy in cdx and pdx models abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-08.
Puleo et al. (Tue,) studied this question.