Development of cell-permeable peptide-based PROTACs targeting estrogen receptor α

Proteolysis-targeting chimera (PROTAC) could selectively degrade target protein and may become a promising strategy for treating estrogen receptor α (ERα) positive breast cancers. Here, we designed penetrated peptide-based PROTACs by constructing an N-terminal lactam cyclic to improve proteolytic stability and cell penetration. We used a lactam cyclic peptide as ERα binding ligand, 6-aminocaproic acid as a linker, and a hydroxylated pentapeptide structure for recruiting E3 ligase to obtain heterobifunctional compounds. The resulting optimized compound I-6 selectively recruited ERα to the E3 ligase complex for promoting the degradation of ERα. Compound I-6 possessed strong effect on MCF-7 cell toxicity (IC50 ∼9.7 μM) and significantly enhanced activities in inducing ERα degradation. Meanwhile, I-6 performed much stronger potency in inhibition of tumors growth than tamoxifen. This work is a successful template to construct PROTACs based on cell-permeable peptides, which could extend the chemical space of PROTACs. [Display omitted] •Synthesis of cell-permeable peptide-based PROTACs targeting estrogen receptor α.•I-6 possessed strong effect on ERα positive cells MCF-7 toxicity (IC50 ∼9.7 μM).•I-6 exhibited membrane penetrability and pro-apoptosis activity and tumor growth inhibitory activities in vivo.•I-6 selectively recruited ERα to the VHL E3 ligase complex, leading to the degradation of ERα in a proteasome-dependent manner.•All results indicated PROTAC I-6 may be a promising candidate which extends the breast cancer therapy.