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Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead

2017; Elsevier BV; Volume: 25; Issue: 1 Linguagem: Inglês

10.1016/j.chembiol.2017.09.010

2451-9456

Daniel P. Bondeson, Blake E. Smith, George M. Burslem, Alexandru D. Buhimschi, John Hines, Saul Jaime‐Figueroa, Jing Wang, Brian D. Hamman, Alexey Ishchenko, Craig M. Crews,

Ubiquitin and proteasome pathways

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 chimeras (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 >50 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.