A selective estrogen receptor covalent antagonist
H3B-5942 is a selective estrogen receptor covalent antagonist (SERCA).1 It covalently modifies cysteine 530 in the ligand binding domain of wild-type estrogen receptor α (ERα) and ERαY537S. HB-5942 inhibits expression of the ERα target genes GREB1 and TFF1 in MCF-7 cells overexpressing wild-type ERα (IC50s = 2.74 and 1.3 nM, respectively) or the mutant receptors ERαY537S (IC50s = 29.38 and 19.4 nM, respectively), ERαY537N (IC50s = 8.14 and 6.1 nM, respectively), ERαY537C (IC50s = 12.19 and 9.5 nM, respectively), or ERαD538G (IC50s = 24.87 and 4 nM, respectively), which are active independent of estradiol. It inhibits the growth of MCF-7 cells overexpressing wild-type ERα or ERαY537S (GI50s = 1.3 and 8.3 nM, respectively). H3B-5942 reduces tumor growth in an MCF-7 mouse xenograft model and an ERαY537S/WT ST941 patient-derived xenograft (PDX) mouse model in a dose-dependent manner.
1.Puyang, X., Furman, C., Zheng, G.Z., et al.Discovery of selective estrogen receptor covalent antagonists for the treatment of ERαWT and ERαMUT breast cancerCancer Discov.8(9)1176-1193(2018)
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