American Association for Cancer Research
21598290cd171229-sup-191892_2_supp_4827115_pbbbt0.pptx (1.13 MB)

Figures S20-S23 from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

Download (1.13 MB)
posted on 2023-04-03, 21:44 authored by Xiaoling Puyang, Craig Furman, Guo Zhu Zheng, Zhenhua J. Wu, Deepti Banka, Kiran Aithal, Sergei Agoulnik, David M. Bolduc, Silvia Buonamici, Benjamin Caleb, Subhasree Das, Sean Eckley, Peter Fekkes, Ming-Hong Hao, Andrew Hart, René Houtman, Sean Irwin, Jaya J. Joshi, Craig Karr, Amy Kim, Namita Kumar, Pavan Kumar, Galina Kuznetsov, Weidong G. Lai, Nicholas Larsen, Crystal Mackenzie, Lesley-Ann Martin, Diana Melchers, Alyssa Moriarty, Tuong-Vi Nguyen, John Norris, Morgan O'Shea, Sunil Pancholi, Sudeep Prajapati, Sujatha Rajagopalan, Dominic J. Reynolds, Victoria Rimkunas, Nathalie Rioux, Ricardo Ribas, Amy Siu, Sasirekha Sivakumar, Vanitha Subramanian, Michael Thomas, Frédéric H. Vaillancourt, John Wang, Suzanne Wardell, Michael J. Wick, Shihua Yao, Lihua Yu, Markus Warmuth, Peter G. Smith, Ping Zhu, Manav Korpal

H3B-5942 in combination with palbocyclib shows synergy in vitro and in vivo


H3 Biomedicine, Inc.

Breast Cancer Now Toby Robins Research Centre




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 ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S 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 ERαWT and ERαMUT 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 ERαWT and ERαMUT, 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

Usage metrics

    Cancer Discovery



    Ref. manager