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Drug Discov Today Technol. 2019 Apr;31:15-27. doi: 10.1016/j.ddtec.2019.01.002. Epub 2019 Feb 13.

PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future.

Author information

1
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
2
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA. Electronic address: craig.crews@yale.edu.

Abstract

The majority of currently used therapeutics are small molecule-based and utilize occupancy-driven pharmacology as the mode of action (MOA), in which the protein function is modulated via temporary inhibition. New modalities that operate using alternative MOAs are essential for tapping into the "undruggable" proteome. The PROteolysis Targeting Chimera (PROTAC) technology provides an attractive new approach that utilizes an event-driven MOA. Small molecule-based heterobifunctional PROTACs modulate protein target levels by hijacking the ubiquitin-proteasome system to induce degradation of the target. Here, we address important milestones in the development of the PROTAC technology, as well as emphasize key findings from this previous year and highlight future directions of this promising drug discovery modality.

PMID:
31200855
PMCID:
PMC6578591
[Available on 2020-04-01]
DOI:
10.1016/j.ddtec.2019.01.002
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