Modulation of estrogen activity and/or synthesis has been the mainstay therapeutic strategy for estrogen receptor (ER)-positive breast cancer. Fulvestrant, which provides superior clinical benefit over aromatase inhibitors and selective ER modulators, achieves its potent ER signaling inhibition through unique ER degradation activity beyond direct antagonism. Despite this superiority, the efficacy of fulvestrant appears limited by poor drug exposure through intramuscular injection. Up to 50% of ER baseline levels remained after 6 months of fulvestrant treatment. Therefore, an oral ER degrader with optimal pharmacokinetic profile may lead to better convenience and efficacy than fulvestrant. Here we report preclinical characterization of our novel oral ER degrader development candidate, AC682, a chimeric small molecule containing both ligands of ER and E3 ligase discovered with our ACCU-Degron technology. Through engaging E3 ligase and ER simultaneously, AC682 induced potent ER degradation with a sub-nanomolar half-maximal degradation concentration (DC50) in multiple ER-positive breast cancer cell lines tested, including a tamoxifen-resistant long-term estrogen deprived (LTED) cell line and cell lines expressing clinically-relevant ESR1 variants (Y537S and D538G). Proteasome-dependent ER degradation by AC682 peaked after a few hours of treatment, resulting in diminished expression of ER-regulated genes and subsequent cell growth inhibition. In the in vivo setting, oral dosing of AC682 achieved substantial drug exposure and oral bioavailability, with well tolerance in multiple animal species. In estradiol-dependent MCF7 xenograft tumors, oral daily dosing of AC682 led to dose-dependent tumor growth inhibition/regression and concomitant tumor ER protein reduction more than 90% at study termination. In particular, 3 mg/kg oral daily dosing achieved tumor stasis. When administrated in combination with CDK4/6 inhibitor Palbociclib, AC682 showed clear synergy in both the estradiol-dependent MCF7 model and a tamoxifen-resistant MCF7 model. In a patient-derived xenograft model, which bears ESR1 Y537S mutation and is hormone-independent, AC682 significantly inhibited tumor growth whereas fulvestrant only showed weak efficacy. In conclusion, oral chimeric ER degrader AC682 demonstrated robust ER degradation and anti-tumor efficacy in preclinical models, supporting its continued investigation in the clinic.

Citation Format: Wei He, Hui Zhang, Lorena Perkins, Lissette Bouza, Ke Liu, Yimin Qian, Jie Fan. Novel chimeric small molecule AC682 potently degrades estrogen receptor with oral anti-tumor efficacy superior to fulvestrant [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-09.