Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC
Thomas G. Hayhow, Beth Williamson, Mandy Lawson, Natalie Cureton, Erin Braybrooke, Andrew T. Campbell, Rodrigo J. Carbajo, Azadeh Cheraghchi-Bashi, Elisabetta Chiarparin, C. R. Diène, Charlene Fallan, David I. Fisher, Frederick W. Goldberg, Lorna Hopcroft, Philip Hopcroft, Anne Jackson, Jason G. Kettle, Teresa Klinowska, Ulrike Künzel, Gillian M. Lamont, Hilary Lewis, Gareth Maglennon, Scott Martin, Pablo Morentin Gutierrez, Christopher J. Morrow, Myria Nikolaou, J. Willem M. Nissink, Patrick OʼShea, Radosław Polański, Markus Schade, James S. Scott, Aaron Smith, Judith Weber, Joanne Wilson, Bin Yang, Claire Crafter
Abstract
Targeting 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. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.