Thomas G. Hayhow

May 12, 2024 | nature.com | Thomas G. Hayhow |Rodrigo J. Carbajo |David Fisher |Frederick W. Goldberg |Lorna Hopcroft |Philip Hopcroft | +5 more

AbstractTargeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect.