PROTAC is a heterobifunctional molecule containing two small molecule binding moieties. Specifically, PROTACs in cells seek and selectively bind to target proteins. PROTAC then recruits specific E3 ligases to the target protein. Besides, it forms a ternary complex in close proximity to the target protein and E3 ligase. In addition, the E3 ligase subsequently recruits the E2 binding enzyme into the ternary complex. This allows the E2 ligase to ubiquitinate the target protein, then dissociate from the ternary complex, and finally start another catalytic cycle. Moreover, PROTACs have antitumor activity and can degrade estrogen receptors in many different breast cancer cell lines.

In the presence of estradiol, the intracellular level of ERα is downregulated by the ubiquitin/proteasome (UB/26S) pathway. Furthermore, proteasome effects on polyubiquitination of ERα. The degradation is catalyzed by ubiquitin activated by ubiquitin-activating enzyme E1. Meanwhile, E2 binding enzymes bind it to lysine residues via isopeptide bonds and E3 ubiquitin ligases. Estrogen acts by binding to specific receptors, estrogen receptors (ER). Nonetheless, PROTAC-mediated ER degradation reduces the expression of classical regulated ER target genes. It inhibits the cell proliferation of ER-dependent cell lines (MCF7, T47D). Here, we will introduce an oral estrogen receptor PROTAC protein degrader for breast cancer, ARV-471.

ARV-471 is an Estrogen Receptor PROTAC Degrader for Breast Cancer.

Above all, ARV-471 is an oral estrogen receptor PROTAC protein degrader for breast cancer. ARV-471 is a hetero-bifunctional molecule. Importantly, ARV-471 facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex.

Next in importance, ARV-471 leads to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. Particularly, ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~2 nM.

Once again, a single daily oral dose of ARV-471 (3, 10, and 30 mpk) resulted in a significant reduction in tumor volume in estradiol-dependent MCF7 xenografts.

All in all, ARV-471 is an oral estrogen receptor PROTAC protein degrader for breast cancer.


JJ Flanagan, et al. Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer.