Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Abstract

Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy–resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.

FOXA1 O-GlcNAcylation–mediated transcriptional switch governs metastasis capacity in breast cancer

“…S13). Visible changes in the ERα chromatin-binding parameters [GSE178373 ( 36 ), published ChIP-seq dataset generated from MCF-7 cells] in FOXA1 WT and FOXA1 3A -binding sites were observed (fig. S14).…”

Estrogen Receptor α/14-3-3 molecular glues as alternative treatment strategy for endocrine resistant breast cancer

“…4 Therefore, attention has been shifted towards the identification of alternative small-molecule modulators that target ERα outside this ligand binding pocket, like the coregulator binding groove 38 or the ERα/DNA binding interface. 39,40 Novel LBD-targeting drugs can also be advantageous as demonstrated by the ERα CRBN-based PROTAC (ARV-471) 41 and covalent cysteine-530 targeting ERα antagonist (HB-6545) 42 , both being currently evaluated in clinical trials (NCT05654623, NCT03250676, NCT04568902, NCT04288089).…”

Targeting Breast Cancer: An Overlook on Current Strategies

“…H3B-5942 is the first-in-class experimental oral compound showing exquisite selectivity for C530 and antitumor activity superior to fulvestrant therapy in BC xenograft models with ESR1 WT or ESR1 Y37S mutation [ 123 ]. It is known for being the precursor of compound H3B-6545, which was suggested for the potential treatment of endocrine therapy-resistant ERα+ BC harboring wild-type or mutant ESR1 (clinical trials: NCT03250676, NCT04568902, NCT04288089) [ 124 ]. It is noteworthy that the name SERCA must not be confused with sarcoplasmic reticulum (ER/SR) Ca 2+ -ATPase, which possesses the same acronym and is also involved in studies regarding BC [ 125 , 126 , 127 ].…”