H3B-6545 is an oral and selective antagonist of estrogen receptor covalent (SERCA).

H3B-6545 inhibits ERαWT activity and growth of ERαWT -positive breast cancer lines and it also effectively inhibits ERαWT activity and suppresses proliferation of ERαWT -positive breast cancer lines (GI50s: 0.3-0.4, 1.0, 0.5, 5.2, and 0.2 nM for MCF7, HCC1428, BT483, T47D, and CAMA-1 cell lines). H3B-6545 is a first-in-class selective ER covalent antagonist (SERCA). H3B-6545 is a highly selective small molecule. In biochemical and cell-based assays, it also effectively antagonizes wild-type and mutant ERα. In vitro comparisons with the standard of care and other experimental agents confirm, increased cell potency of H3B-6545 under continuous as well as washout treatment conditions [1]. H3B-6545, a member of a novel class of ERα antagonists refers to as selective ER covalent antagonist (SERCA), which inactivates both wild-type and mutant ERα by targeting C530 and enforcing a unique antagonist conformation [1].

H3B-6545 is well tolerated across a broad dose range and at exposures that significantly exceed those required for efficacy in mouse xenograft models. H3B-6545 (once daily; p.o.) treatment, displays effective activity and superior efficacy to fulvestrant in the MCF-7 xenograft model with maximal antitumor activity at doses >10x below the maximum tolerated dose in mice. H3B-6545 displays superior antitumor activity to Tamoxifen and Fulvestrant in patient-derived xenograft models of estrogen receptor-positive breast cancer including models carrying ERα mutations in rats and monkeys [1].