PROteolysis-TArgeting Chimeras (PROTACs) are a powerful class of drugs that selectively degrade the proteins of interest (POIs) through cellular ubiquitination mechanisms. Estrogen receptor α (ERα) plays a vital role in the pathogenesis and treatment of breast cancer. In this work, the DNA-binding domain (DBD) of ERα was selected as the target to avoid drug resistance caused by the ligand-binding domain (LBD) of ERα. The estrogen response element (ERE), a natural DNA sequence binding with DBD of ERα, was chosen as a recognized unit of PROTAC. Therefore, we designed a nucleic acid-conjugated PROTAC, ERE-PROTAC, via a click reaction, in which the ERE sequence recruits ERα and the typical small molecule VH032 recruits the von Hippel-Lindau (VHL) E3 ligase. The proposed ERE-PROTAC showed to efficiently and reversibly degrade ERα in different breast cancer cells by targeting the DBD, indicating its potential to overcome the current resistance caused by LBD mutations.

Chemical Communications

First-in-class metallo-PROTAC as an effective degrader of select Pt-binding proteins

Article

Author: Chonghaile, Tríona Ní ; O'Dowd, Paul D ; Griffith, Darren M ; Sullivan, Graeme P ; Rodrigues, Daniel A

We report the development of the first metallo-PROTAC, specifically a Pt-PROTAC that effectively degrades select Pt(ii)-binding proteins. Metallo-PROTACs will have important applications in identifying metal binding proteins and as chemotherapeutics.

Communications Biology

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

Article

Author: Scott, James S ; Campbell, Andrew ; Gutierrez, Pablo Morentin ; Jackson, Anne ; Cureton, Natalie ; Nikolaou, Myria ; Hayhow, Thomas G ; Polanski, Radoslaw ; Weber, Judith ; Lamont, Gillian ; Lewis, Hilary J ; Hopcroft, Philip ; Fallan, Charlene ; Smith, Aaron ; Wilson, Joanne ; Schade, Markus ; Klinowska, Teresa ; Morrow, Christopher J ; Fisher, David I ; Williamson, Beth ; O'Shea, Patrick ; Diène, Coura R ; Yang, Bin ; Maglennon, Gareth ; Crafter, Claire ; Künzel, Ulrike ; Lawson, Mandy ; Hopcroft, Lorna ; Goldberg, Frederick W ; Braybrooke, Erin L ; Kettle, Jason G ; Nissink, J Willem M ; Martin, Scott ; Carbajo, Rodrigo J ; Cheraghchi-Bashi, Azadeh ; Chiarparin, Elisabetta

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. 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.

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Indication	Highest Phase	Country/Location	Organization	Date
ER-positive/HER2-negative Breast Cancer	Preclinical	KR	EnhancedBio, Inc.Startup	16 Sep 2022

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