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