Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC

• DOI: 10.1038/s42003-024-06238-x
• Publication Date: 2024-05-13T14:01:56Z
• Authors: Thomas G. Hayhow; Beth Williamson; Mandy Lawson; Natalie Cureton; Erin L. Braybrooke; Andrew Campbell; Rodrigo J. Carbajo; Azadeh Cheraghchi...; Elisabetta Chiarp...; Coura R. Diène; Charlene Fallan; David I. Fisher; Frederick W. Gold...; Lorna Hopcroft; Philip Hopcroft; Anne Jackson; Jason G. Kettle; Teresa Klinowska; Ulrike Künzel; Gillian Lamont; Hilary J. Lewis; Gareth Maglennon; Scott Martin; Pablo Morentin Gu...; Christopher J. Mo...; Myria Nikolaou; J. Willem M. Nissink; Patrick O’Shea; Radoslaw Polanski; Markus Schade; James S. Scott; Aaron Smith; Judith Weber; Joanne Wilson; Bin Yang; Claire Crafter
• Keywords: Linker; Protein Degradation; Ex vivo

Abstract Targeting the estrogen receptor alpha (ERα) pathway is validated in clinic as an effective means to treat ER+ breast cancers. Here we present development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation ER antagonism cancer cell lines. However, upon dosing compound vivo observe - disconnect. lower than expected based on data. Investigation into potential causes for reduced maximal reveals that metabolic instability linker generates metabolites compete binding full PROTAC, limiting degradation. This observation highlights requirement metabolically stable PROTACs ensure efficacy thus optimisation should be key consideration when designing PROTACs.