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

Mutations in estrogen receptor alpha (ER alpha) 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 ERa signaling, there remains a critical need to develop the next generation of ERa antagonists that can overcome aberrant ER alpha activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ER alpha by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ER alpha 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 ER alpha(WT) and ER alpha(MUT) cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ER alpha(WT) and ER alpha(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 ER alpha(WT) and ER alpha(MUT) cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ER alpha covalent antagonists with an improved profile over SoCs. SIGNIFICANCE: Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ER alpha. SERCA H3B-5942 engages C530 of both ER alpha(WT) and ER alpha(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. (C) 2018 AACR.