Data from Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα&lt;sup&gt;WT&lt;/sup&gt; and ERα&lt;sup&gt;MUT&lt;/sup&gt; Breast Cancer

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

doi:10.1158/2159-8290.c.6546874

Abstract

<div>AbstractMutations 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</div>

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