Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERα<sup>WT</sup> and ERα<sup>MUT</sup> Breast Cancer.
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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). <i>In vitro</i> comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERα<sup>WT</sup> and ERα<sup>MUT</sup> cell lines. <i>In vivo</i>, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERα<sup>WT</sup> and ERα<sup>Y537S</sup> 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 ERα<sup>WT</sup> and ERα<sup>MUT</sup> 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.<b>Significance:</b> Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERα<sup>WT</sup> and ERα<sup>MUT</sup>, promotes a unique antagonist conformation, and demonstrates improved <i>in vitro</i> and <i>in vivo</i> activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. <i>Cancer Discov; 8(9); 1176-93. ©2018 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 1047</i>.
Cell Line, Tumor
Estrogen Receptor alpha
Protein Kinase Inhibitors
Drug Screening Assays, Antitumor
Xenograft Model Antitumor Assays
Drug Resistance, Neoplasm
Estrogen Receptor Antagonists
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Cancer discovery, 2018, 8 (9), pp. 1176 - 1193