Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway

Abstract

Aberrantly elevated steroid receptor coactivator‐1 (SRC‐1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC‐1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N‐degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC‐1 in cells through the N‐degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC‐1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC‐1 degrader can be an invaluable chemical tool in the studies of SRC‐1 functions. Moreover, our findings suggest PROTACs based on the N‐degron pathway as a widely useful strategy to degrade disease‐relevant proteins.

Peptide-based inhibitors of protein–protein interactions: biophysical, structural and cellular consequences of introducing a constraint

“…Nonetheless, signicant barriers to the use of linear-peptide ligands have been surpassed using this class of peptides, leading to candidates that have entered clinical trials. 11,122 The development of constrained peptides to target an increasingly broad range of targets [123][124][125] alongside their integration into proteolysis targeting chimeras 126 ensures they can condently be predicted to remain an important class of compounds in chemical biology and drug discovery research.…”

Applications of Bacterial Degrons and Degraders — Toward Targeted Protein Degradation in Bacteria

“…The first PROTACs had peptidic binding moieties; however, because of the relatively poor permeability and stability for peptides, more recent PROTACs now are constructed from small molecules (Sakamoto et al, 2001;Schneekloth et al, 2004;Ishikawa et al, 2020). Nonetheless, the limitations of peptide ligands may in principle be obviated with peptidomimetics, chemical modifications, or fusions with cell-penetrating peptides (Jiang et al, 2018;Lu et al, 2018;Au et al, 2020;Jin J. et al, 2020;Lee et al, 2020;Ma D. et al, 2020). Due to the low toxicity of peptides, their large binding surfaces (which can help overcome the effect of mutations in target proteins), and the possibility of designing multiple potential ligands based on structures of protein complexes, peptide-based PROTACs are still used (Au et al, 2020;Jin J. et al, 2020).…”

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

“…This approach briefly leverages the N-end rule pathway, a system in which the amino acid residues occupying the N-terminal position of a protein are subjected to processes such as deamidation and arginylation, and are eventually recognized by the UBR1 E3 ligase and targeted for degradation in the proteasome [ 12 ]. In this contribution, Lee et al [ 169 ] utilized the tetrapeptide N-terminal degron LRAA as a UBR1 binder, to build a chimera in which the target ligand is YL2, a helical motif that binds the steroid receptor coactivator-1 (SRC1), mimicking the specific interaction between the Signal Transducer and Activator of Transcription (STAT6) and SRC1. SRC1 regulates the expression of multiple additional transcription factors, and its levels correlate with metastasis and recurrence [ 170 ].…”