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^WT and ERα^MUT lines with GI50 values of 0.5, 2, and 30 nmol/L in the MCF7-Parental, MCF7-LTED-ERα^WT, and MCF7-LTED-ERα^Y537C 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^WT line. In the presence of E2, H3B-5942 shows a significant dose-dependent decrease in ER-mediated transactivation in all cell lines tested^[1].

In vivo, H3B-5942 demonstrates significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer^[1].

• Animal Models

  Mice bearing PDX tumors representing Erα(Y537S/WT) breast cancer

• Dosages

  3, 10, 30, 100, and 200 mg/kg

• Administration

  PO