Journal
SCIENCE ADVANCES
Volume 7, Issue 15, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg1950
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Funding
- Bloodwise [12051]
- MRC [MR/J000612/1]
- Wellcome Trust [099246/Z/12/Z]
- Wellcome Trust [099246/Z/12/Z] Funding Source: Wellcome Trust
- MRC [MR/J000612/1] Funding Source: UKRI
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Intracellular antibodies can be used for target validation or developing small-molecule surrogates, such as through Abd technology. Researchers have identified a series of anti-LMO2 Abd compounds that bind to the same location as an inhibitory anti-LMO2 intracellular antibody, demonstrating potential applications in challenging protein research.
Intracellular antibodies are tools that can be used directly for target validation by interfering with properties like protein-protein interactions. An alternative use of intracellular antibodies in drug discovery is developing small-molecule surrogates using antibody-derived (Abd) technology. We previously used this strategy with an in vitro competitive surface plasmon resonance method that relied on high-affinity antibody fragments to obtain RAS-binding compounds. We now describe a novel implementation of the Abd method with a cell-based intracellular antibody-guided screening method that we have applied to the chromosomal translocation protein LMO2. We have identified a chemical series of anti-LMO2 Abd compounds that bind at the same LMO2 location as the inhibitory anti-LMO2 intracellular antibody combining site. Intracellular antibodies could therefore be used in cell-based screens to identify chemical surrogates of their binding sites and potentially be applied to any challenging proteins, such as transcription factors that have been considered undruggable.
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