H3B-5942 is a selective, irreversible and orally active estrogen receptor covalent antagonist, inactivates both wild-type and mutant ERα by targeting Cys530, with Kis of 1 nM and 0.41 nM, respectively. H3B-5942 reduces ERα target gene GREB1, shows potent antitumor activity both in multiple cell lines or animals bearing ERαWT or ERα mutations[1].
H3B-5942 is a selective and irreversible estrogen receptor covalent antagonist, inactivates both wild-type and mutant ERα by targeting Cys530, with Kis of 1 nM and 0.41 nM, respectively[1].H3B-5942 elevates ERα protein level distinct from SERMs/SERD, blocks ERα-dependent transcription in breast cancer cells. H3B-5942 (0.01-10 μM) reduces ERα target gene GREB1 in MCF7-ERαWT, various MCF7-ERαMUT lines, and the PDX-ERαY537S/WT line[1]. H3B-5942 also decreases proliferation of MCF7-Parental, MCF7-LTED-ERαWT, and MCF7-LTED-ERαY537C lines with GI50s of 0.5, 2, and 30 nM, respectively. H3B-5942 (10-25 nM) in combination with CDK4/6 inhibitors (≥25 pM) has synergic inhibitory effect on multiple cell lines bearing ERαWT or clinically frequent ERα mutations[1].
H3B-5942 (1, 3, 10, or 30 mg/kg, p.o, q.d.) dose-dependently inhibits tumor growth in MCF7 xenograft model in athymic female nude mice. H3B-5942 (3, 10, 30, 100, and 200 mg/kg, p.o, q.d.) exhibits similar anti-tumor activity in the ERαY537S/WT ST941 model in athymic female nude mice[1].
[1]. Puyang X, et al. Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer. Cancer Discov. 2018 Sep;8(9):1176-1193.