Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer PMID: 29991605

ADC Targets in Oncology

2026-04-10

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Cancer Discov. 2018 Sep;8(9):1176-1193. doi: 10.1158/2159-8290.CD-17-1229.

Xiaoling Puyang ^# ¹ , Craig Furman ^# ¹ , Guo Zhu Zheng ^# ¹ , Zhenhua J Wu ¹ , Deepti Banka ¹ , Kiran Aithal ² , Sergei Agoulnik ³ , David M Bolduc ¹ , Silvia Buonamici ¹ , Benjamin Caleb ¹ , Subhasree Das ¹ , Sean Eckley ³ , Peter Fekkes ¹ , Ming-Hong Hao ¹ , Andrew Hart ³ , René Houtman ⁴ , Sean Irwin ¹ , Jaya J Joshi ¹ , Craig Karr ¹ , Amy Kim ¹ , Namita Kumar ³ , Pavan Kumar ¹ , Galina Kuznetsov ³ , Weidong G Lai ³ , Nicholas Larsen ¹ , Crystal Mackenzie ¹ , Lesley-Ann Martin ⁵ , Diana Melchers ⁴ , Alyssa Moriarty ⁶ , Tuong-Vi Nguyen ¹ , John Norris ⁷ , Morgan O'Shea ¹ , Sunil Pancholi ⁵ , Sudeep Prajapati ¹ , Sujatha Rajagopalan ² , Dominic J Reynolds ¹ , Victoria Rimkunas ¹ , Nathalie Rioux ¹ , Ricardo Ribas ⁵ , Amy Siu ³ , Sasirekha Sivakumar ² , Vanitha Subramanian ¹ , Michael Thomas ¹ , Frédéric H Vaillancourt ¹ , John Wang ¹ , Suzanne Wardell ⁷ , Michael J Wick ⁶ , Shihua Yao ¹ , Lihua Yu ¹ , Markus Warmuth ¹ , Peter G Smith ¹ , Ping Zhu ⁸ , Manav Korpal ⁸

Affiliations

Abstract

Mutations in Estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast Cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective Estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERα^WT and ERα^MUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERα^WT and ERα^Y537S breast Cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERα^WT and ERα^MUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs.Significance: Nearly 30% of endocrine therapy-resistant breast Cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERα^WT and ERα^MUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176-93. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.