Abstract
Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality. By co-opting protein degradation pathways, TPD facilitates complete removal of the protein molecules from within or outside the cell. While the pioneering Proteolysis-Targeting Chimera (PROTAC) technology and molecular glues hijack the ubiquitin-proteasome system, newer modalities co-opt autophagy or the endo-lysosomal pathway. Using this mechanism, TPD is posited to largely expand the druggable space far beyond small-molecule inhibitors. In this review, we discuss the major advances in TPD, highlight our current understanding, and explore outstanding questions in the field.
Highlights
Edited by Phyllis HansonOf late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality
All eyes lie on these clinical candidates as they pave the way for future drugs of this class
This field is in its formative years with much to be learned and even more to be discovered
Summary
Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality. While the pioneering Proteolysis-Targeting Chimera (PROTAC) technology and molecular glues hijack the ubiquitin-proteasome system, newer modalities co-opt autophagy or the endo-lysosomal pathway Using this mechanism, TPD is posited to largely expand the druggable space far beyond small-molecule inhibitors. As compared with VHL, the promiscuous CRBN has been shown to be more accepting of neosubstrate degradation far [69] This promiscuity is a bit of a double-edged sword in that PROTACs incorporating phthalimides are not as selective and can induce degradation of nonintended neosubtrates such as G1 to S phase transition protein 1, a protein identified as a common off target of IMiD-based degraders [29, 70]. The newly identified E3 binders may require optimization for specificity, they illustrate that E3 ligases are generally susceptible to hijacking for TPD Whether these covalent PROTACs can degrade their targets in a substoichiometric fashion has yet to be formally established, their surprising potency strongly hints at a catalytic mechanism (Fig. 1). As some E3 ligases have been shown to form K63 ubiquitin chains, it may be possible to recruit these E3 ligases and promote lysosomal degradation as opposed to proteasomal degradation
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