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@ARTICLE{Schwalm:289592,
author = {M. P. Schwalm$^*$ and K. Saxena and S. Müller and S.
Knapp$^*$},
title = {{L}uciferase- and {H}alo{T}ag-based reporter assays to
measure small-molecule-induced degradation pathway in living
cells.},
journal = {Nature protocols},
volume = {19},
number = {8},
issn = {1754-2189},
address = {Basingstoke},
publisher = {Nature Publishing Group},
reportid = {DKFZ-2024-00825},
pages = {2317-2357},
year = {2024},
note = {2024 Aug;19(8):2317-2357},
abstract = {The rational development of small-molecule degraders (e.g.,
proteolysis targeting chimeras) remains a challenge as the
rate-limiting steps that determine degrader efficiency are
largely unknown. Standard methods in the field of targeted
protein degradation mostly rely on classical, low-throughput
endpoint assays such as western blots or quantitative
proteomics. Here we applied NanoLuciferase- and
HaloTag-based screening technologies to determine the
kinetics and stability of small-molecule-induced ternary
complex formation between a protein of interest and a
selected E3 ligase. A collection of live-cell assays were
designed to probe the most critical steps of the degradation
process while minimizing the number of required expression
constructs, making the proposed assay pipeline flexible and
adaptable to the requirements of the users. This approach
evaluates the underlying mechanism of selective target
degraders and reveals the exact characteristics of the
developed degrader molecules in living cells. The protocol
allows scientists trained in basic cell culture and
molecular biology to carry out small-molecule
proximity-inducer screening via tracking of the ternary
complex formation within 2 weeks of establishment, while
degrader screening using the HiBiT system requires a
CRISPR-Cas9 engineered cell line whose generation can take
up to 3 months. After cell-line generation, degrader
screening and validation can be carried out in
high-throughput manner within days.},
subtyp = {Review Article},
cin = {FM01},
ddc = {610},
cid = {I:(DE-He78)FM01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38637703},
doi = {10.1038/s41596-024-00979-z},
url = {https://inrepo02.dkfz.de/record/289592},
}