Abstract LB439: HP568, a highly potent and orally bioavailable ER PROTAC for breast cancer treatment, currently undergoing phase 1/2 clinical studies

Abstract HP568, an estrogen receptor (ER)-targeting proteolysis-targeting chimera (PROTAC) degraders that enhances the interaction between ER and an E3 ligase complex, resulting in ubiquitylation and subsequent proteasome mediated degradation. This compound exhibits high potency against both wild-type (half-maximal degradation concentration (DC50) < 1 nM) and ER mutants (DC50s < 5 nM), selectively inhibiting the proliferation of ER-dependent breast cancer cell lines in vitro. With an excellent ADME profile, it outperforms current ER-targeting PROTACs. In direct efficacy comparisons with ARV-471, HP568 shows superior, dose-dependent tumor growth inhibition (TGI) of 90%-123%, well correlated with drug exposure and pharmacodynamic biomarkers. Importantly, in models resistant to fulvestrant, including MCF-7 ERα D538G and Y537S cell-derived CDX mice, it demonstrates significant dose-dependent TGI (29%-115%) while maintaining favorable safety profiles. Moreover, HP568 demonstrates synergistic effects when combined with a CDK4/6 inhibitor. Secondary pharmacology and animal toxicity studies support its excellent safety and tolerability, together with the pharmacodynamic data, positioning it as a potential best-in-class ER-targeting degrader. The IND applications for HP568 have been approved by the China National Medical Products Administration and the U.S. FDA. An ongoing Phase 1/2 study (CTR20244203, NCT06757335) is currently being conducted in China for patients with ER+/HER2- advanced breast cancer. The Phase 1 dose escalation part of the study is assessing safety, pharmacokinetics, pharmacodynamics, preliminary antitumor activity, and potential efficacy biomarkers. The Phase 2 expansion will evaluate HP568 both as a monotherapy and in combination with a CDK4/6 inhibitor.HP568 structure will not be disclosed. Citation Format: Jing Li, Zhilin Tu, Luchan Deng, Zhipeng Quan, Wu Du, Xinghai Li. HP568, a highly potent and orally bioavailable ER PROTAC for breast cancer treatment, currently undergoing phase 1/2 clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB439.