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Emerging degrader technologies engaging lysosomal pathways.

Yu DingDong XingYiyan FeiBoxun Lu
Published in: Chemical Society reviews (2022)
Targeted protein degradation (TPD) provides unprecedented opportunities for drug discovery. While the proteolysis-targeting chimera (PROTAC) technology has already entered clinical trials and changed the landscape of small-molecule drugs, new degrader technologies harnessing alternative degradation machineries, especially lysosomal pathways, have emerged and broadened the spectrum of degradable targets. We have recently proposed the concept of autophagy-tethering compounds (ATTECs) that hijack the autophagy protein microtubule-associated protein 1A/1B light chain 3 (LC3) for targeted degradation. Other groups also reported degrader technologies engaging lysosomal pathways through different mechanisms including AUTACs, AUTOTACs, LYTACs and MoDE-As. In this review, we analyse and discuss ATTECs along with other lysosomal-relevant degrader technologies. Finally, we will briefly summarize the current status of these degrader technologies and envision possible future studies.
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