Hydrophobic Tagging-Mediated Degradation of Transcription Coactivator SRC-1

Abstract

Steroid receptor coactivator-1 (SRC-1) is a transcription coactivator playing a pivotal role in mediating a wide range of signaling pathways by interacting with related transcription factors and nuclear receptors. Aberrantly elevated SRC-1 activity is associated with cancer metastasis and progression, and therefore, suppression of SRC-1 is emerging as a promising therapeutic strategy. In this study, we developed a novel SRC-1 degrader for targeted degradation of cellular SRC-1. This molecule consists of a selective ligand for SRC-1 and a bulky hydrophobic group. Since the hydrophobic moiety on the protein surface could mimic a partially denatured hydrophobic region of a protein, SRC-1 could be recognized as an unfolded protein and experience the chaperone-mediated degradation in the cells through the ubiquitin–proteasome system (UPS). Our results demonstrate that a hydrophobic-tagged chimeric molecule is shown to significantly reduce cellular levels of SRC-1 and suppress cancer cell migration and invasion. Together, these results highlight that our SRC-1 degrader represents a novel class of therapeutic candidates for targeting cancer metastasis. Moreover, we believe that the hydrophobic tagging strategy would be widely applicable to develop peptide-based protein degraders with enhanced cellular activity.

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

“…Unfolded or misfolded proteins expose hydrophobic regions that signal for recruitment of E3 ligases to degrade unwanted POIs in a proteasome-dependent fashion. Several studies have mimicked protein unfolding by labeling specific targets with low molecular weight hydrophobic tags to promote their destruction [ 81 , 82 , 83 , 84 , 85 ]. This modality has been applied to degrade the pseudokinase Her3, an undruggable target implicated in breast, ovarian and non-small cell lung cancers, by bifunctional molecules consisting of a covalent Her3 targeting small molecule linked to a hydrophobic adamantane moiety [ 82 ].…”

“…Using hydrophobic tagging, the lead degrader compound selectively killed triple negative breast cancer cells in vitro and in vivo, whereas existing EZH2 inhibitors fail to do so [ 84 ]. Another hydrophobic tagged dimeric molecule was shown to reduce cellular levels of SRC-1, a transcription co-activator, which in turn suppressed cancer cell migration and invasion [ 83 ]. A further successful application of this approach has been demonstrated by Gustafson et al [ 85 ].…”

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

“…TX2-121-1 ( Figure 2 B) is another bifunctional degrader which leads to partial degradation of Her3 and reduction in Her3-dependant signaling [ 41 ]. More examples are discussed in references [ 42 , 43 , 44 ].…”

“…TX2-121-1 (Figure 2B) is another bifunctional degrader which leads to partial degradation of Her3 and reduction in Her3-dependant signaling [41]. More examples are discussed in references [42][43][44]. Another approach to protein degradation is based on the attachment of hydrophobic labels to the desired inhibitors.…”

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

“…2) is another bifunctional degrader which leads to partial degradation of Her3 and reduction of Her3-dependant signalling [42]. More examples are discussed in the following references [43][44][45]. In the past few years, increasing interest to target HDACs using the PROTAC technology developed.…”