Discovery of Selective Estrogen Receptor Covalent Antagonists (SERCAs) for the treatment of ERa(WT) and ERa(MUT) breast cancer. [Research Articles]

Mutations in estrogen receptor alpha (ERa) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Since 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 ERa activity. Through our drug discovery efforts, we identified H3B-5942 which covalently inactivates both wild-type and mutant ERa by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERa antagonist referred to as Selective Estrogen Receptor Covalent Antagonists (SERCAs). In vitro comparisons of H3B-5942 with standard of care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERa(WT) and ERa(MUT) cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERa(WT) and ERa(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 ERa(WT) and ERa(MUT) cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERa covalent antagonists with an improved profile over SoCs.

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