H3B-6545 Hydrochloride is a selective, oral estrogen receptor covalent antagonist (SERCA).

H3B-6545 is a highly selective small molecule that inhibits both wild-type (ERαWT) and mutant estrogen receptors (ERα), demonstrating potent activity against ERαWT-positive breast cancer cell lines (MCF7, HCC1428, BT483, T47D, and CAMA-1) with GI50s of 0.2-5.2 nM. It shows superior efficacy in biochemical and cell-based assays compared to standard treatments and other experimental agents, under continuous and washout conditions. H3B-6545 uniquely targets C530, enforcing a specific antagonist conformation, and is classified as a selective ER covalent antagonist (SERCA), representing a first-in-class therapeutic approach.

Administered orally once daily, H3B-6545 demonstrates potent and superior anti-tumor efficacy compared to fulvestrant in the MCF-7 xenograft model, achieving maximal effectiveness at doses notably lower than the maximum tolerated dose in mice. Furthermore, H3B-6545 exhibits enhanced anti-tumor effects over Tamoxifen and Fulvestrant in patient-derived xenograft models of estrogen receptor-positive breast cancer, including those with ERα mutations, across various species including rats and monkeys. Notably, H3B-6545 is well-tolerated across a wide dosage range, maintaining significant efficacy at exposures well above those necessary in mouse xenograft models.