A cell-based screening method using an intracellular antibody for discovering small molecules targeting the translocation protein LMO2.

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ICR Authors

Raynaud, Florence
 Rabbitts, Terence

Authors

Bery, N
Bataille, CJR
Russell, A
Hayes, A
Raynaud, F
Milhas, S
Anand, S
Tulmin, H
Miller, A
Rabbitts, TH

Document Type

Journal Article

Date

2021-04-09

Date Accepted

2021-02-19

Abstract

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.

Citation

Science advances, 2021, 7 (15)

DOI

10.1126/sciadv.abg1950

URI

https://repository.icr.ac.uk/handle/internal/4562

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

AMER ASSOC ADVANCEMENT SCIENCE

ISSN

2375-2548

eISSN

2375-2548

Collections

Cancer Therapeutics

Research Team

Chromosomal Translocations and Intracellular Antibody Therapeutics
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Chromosomal Translocations and Intracellular Antibody Therapeutics
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)

Notes