[CAS NO. 2052128-15-9]  H3B-5942

H3B-5942 covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. Upon binding to ERα, H3B-5942 triggers global DNA binding of ERα to ERE-containing promoter and enhancer regions and induces a transcriptionally repressive conformation of ERα by evicting coactivators. H3B-5942 demonstrates potent antiproliferative activity in a panel of ERα and ERα lines with GI50 values of 0.5, 2, and 30 nmol/L in the MCF7-Parental, MCF7-LTED-ERα, and MCF7-LTED-ERα lines, respectively. In the absence of E2, H3B-5942 shows no significant impact on ER-mediated transcription in the MCF7-Parental (endocrine therapy-sensitive) and MCF7-LTED-ERαY537C lines but does result in a 1.5-fold (P = 0.03) increase in the MCF7-LTED-ERα line. In the presence of E2, H3B-5942 shows a significant dose-dependent decrease in ER-mediated transactivation in all cell lines tested.