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

Abstract

Mutations in estrogen receptor alpha (ER) 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 ER signaling, there remains a critical need to develop the next generation of ER antagonists that can overcome aberrant ER activity. Through our drug discovery efforts, we identified H3B-5942 which covalently inactivates both wild-type and mutant ER by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ER antagonist referred to as Selective Estrogen Receptor Covalent Antagonists (SERCAs).In vitro comparisons of H3B-5942 with standard of care (SoC) 10, 2018; DOI: 10.1158/2159-8290.CD-17-1229 3Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on July SignificanceNearly 30% of endocrine-therapy resistant breast cancer metastases harbor constitutively activating mutations in ER. Selective Estrogen Receptor Covalent Antagonist (SERCA) H3B-5942 engages C530 of both ER WT and ER MUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over standard of care (SoC) agents.Importantly, single agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors.

Estrogen Receptor Covalent Antagonists: The Best Is Yet to Come

“…Additional modifications in the core scaffold aimed at improving stability led to the discovery of H3B-5942, a first-in-class orally available selective ER covalent antagonist (SERCA). As intended, H3B-5942 showed exquisite selectivity for C530 (34) and demonstrated stability against other nucleophiles, such as following glutathione addition.…”

“…One hypothesis is that covalent engagement with the cysteine loop of ERa may stabilize this region of the protein, resulting in a different pattern of coregulator recruitment compared with SERMs. Assessment of coregulator interactions using two independent methods, however, did not yield significant differences in global coregulator recruitment between covalent and noncovalent antiestrogens (34). The major limitation of the analysis was that interaction of the ERa-ligand complex with various coregulator peptides was monitored under nonphysiological conditions.…”

“…Right, the chemical structures of H3B-5942 and 4-OHT. possibility, site-specific mutation of C530 to either C530A or C530S results in a considerable loss of sensitivity to H3B-5942 (34). This finding in itself may pose a challenge for this class of small-molecule antagonists of ERa because we (34) and others (32) have shown C530A/S mutations are functionally tolerated and exhibit no compromise in estradiol-stimulated transcriptional activation profiles relative to wild-type ERa.…”

“…In addition to enhancing the residence time and significantly increasing efficacy in the ERa Y537S/WT mutant model relative to SOCs, engagement with C530 also promoted a unique conformation in both wild-type and mutant ERa relative to the known ER conformations induced by SOC and experimental agents. The conformation of ERa induced by H3B-5942 resulted in differentiated biology as little/no agonist activity was noted in the endometrial carcinoma cell line under the specific assay conditions applied (34). It is currently unclear why SERCA H3B-5942 lacks the agonist activity in the endometrial carcinoma setting that 4-OHT exhibits.…”

Emerging data and future directions for CDK4/6 inhibitor treatment of patients with hormone receptor positive HER2‐non‐amplified metastatic breast cancer

“…H3B‐5942 covalently inactivates both wild‐type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation resulting in antitumor activity in vitro and in vivo . Additionally, the efficacy of H3B‐5942 was further improved in combination with palbociclib …”