Design and optimization of Oestrogen Receptor PROTACs based on 4-hydroxytamoxifen

26 May 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


In the last four decades, treatment of oestrogen receptor positive (ER+) breast cancer (BCa), has focused on targeting the estrogenic receptor signaling pathway. This signaling function is pivotal to sustain cell proliferation. Tamoxifen, a competitor inhibitor of oestrogen has played a major role in therapeutics. However, primary and acquired resistance to hormone blockade occurred in a large subset of these cancers, and new approaches were urgently needed. Aromatase inhibitors and receptor degraders were approved and alternatively used. Yet, resistance appears in the metastatic setting. Here we report the design and synthesis of a series of proteolysis targeting chimeras (PROTACs) that induce the degradation of estrogen receptor alpha in breast cancer MCF-7 (ER+) cells at nanomolar concentration. Using a warhead based on 4-hydroxitamoxifen, bifunctional degraders recruiting either cereblon or the Von Hippel Lindau E3 ligases were synthesized. Our efforts resulted in the discovery of TAM-VHL-1, a potent ERα degrader (DC50: 4.5 nM) that we envisage as a useful tool for biology study and a platform for potential therapeutics.


Oestrogen Receptor
Protein degraders

Supplementary materials

Design and optimization of Oestrogen Receptor PROTACs based on 4-hydroxytamoxifen. Supplementary material.
Figure S1, Synthesis of TAM-PO-3-Me, 1H and 13C NMR of all new compounds


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.