Lessons in PROTAC design from selective degradation with a promiscuous warhead
By Daniel P. Bondeson, Blake E. Smith, George M. Burslem, A. Buhimschi, J. Hines, S. Jaime-Figueroa, Jing Wang, B. Hamman, Alexey Ishchenko, C. Crews. Cell Chemical Biology, 2017
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Summary Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule Proteolysis Targeting Chimera (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >100 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small molecule inhibitors.
Subfields: Electrical and Electronic Engineering, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/da278126df38a258e4f975532628937438ad88e5
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Citations in the corpus
- Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, positive): “As we come to understand this new technology better, it is clear that protein-protein contacts between the neo-substrate and E3 complex are a crucial determinant of PROTAC success, as shown in Figure 2 (Bondeson et al., 2018; Gadd et al., 2017; Nowak et al., 2018; Smith et al., 2019; Zorba et al., 2”
- Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs (2022, background): “Furthermore, recent studies have re-ported that ternary complex binding af fi nities do not always correlate with target protein cellular degradation (20, 21), indicating that although TPD always requires ternary complex formation, ternary complex formation does not always lead to TPD, suggesting…”
- PROteolysis TArgeting Chimeras (PROTACs) - Past, Present and Future (2019, background): “A foretinib-based PROTAC, displaying low binary binding affinity towards the kinase p38α (Kd = 11 μM), could nonetheless potently induce its degradation (DC50 = 210 nM, Dmax = 91%) [78].”
- Plasticity in binding confers selectivity in ligand induced protein degradation (2018, neutral): “In general, degraders have been found to exhibit different efficacy and selectivity profiles depending on the nature of the E3-moiety used, sometimes exhibiting improved selectivity over the parental target-moiety 27,28,30 .”