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Updated: Jun 28, 2025
Novel RNA-Binding Proteins Isolation by the RaPID Methodology
Published on: September 30, 2016
mRNA Display Identifies Potent, Paralog-Selective Peptidic Ligands for ARID1B
Gregor S Cremosnik1, Yannick Mesrouze2, Patrik Zueger1
1Global Discovery Chemistry, Novartis Biomedical Research, CH-4056 Basel, Switzerland.
Abstract:
The ARID1A and ARID1B subunits are mutually exclusive components of the BAF variant of SWI/SNF chromatin remodeling complexes. Loss of function mutations in ARID1A are frequently observed in various cancers, resulting in a dependency on the paralog ARID1B for cancer cell proliferation. However, ARID1B has never been targeted directly, and the high degree of sequence similarity to ARID1A poses a challenge for the development of selective binders. In this study, we used mRNA display to identify peptidic ligands that bind with nanomolar affinities to ARID1B and showed high selectivity over ARID1A. Using orthogonal biochemical, biophysical, and chemical biology tools, we demonstrate that the peptides engage two different binding pockets, one of which directly involves an ARID1B-exclusive cysteine that could allow covalent targeting by small molecules. Our findings impart the first evidence of the ligandability of ARID1B, provide valuable tools for drug discovery, and suggest opportunities for the development of selective molecules to exploit the synthetic lethal relationship between ARID1A and ARID1B in cancer.
Insights
Researchers identified ARID1B-selective peptides, offering new cancer drug targets. These peptides bind ARID1B, a paralog of ARID1A, crucial for cancer cell growth when ARID1A is mutated.
Area of Science:
- Chromatin remodeling complexes
- Cancer biology
- Drug discovery
Background:
- ARID1A and ARID1B are subunits of SWI/SNF chromatin remodeling complexes.
- ARID1A mutations are common in cancer, leading to ARID1B dependency for proliferation.
- ARID1B remains an untargeted paralog due to high sequence similarity with ARID1A.
Purpose of the Study:
- To identify selective ligands for ARID1B.
- To explore ARID1B as a potential drug target.
- To investigate the synthetic lethal relationship between ARID1A and ARID1B in cancer.
Main Methods:
- Utilized mRNA display to discover peptidic ligands.
- Employed biochemical, biophysical, and chemical biology techniques for validation.
- Assessed binding affinity and selectivity against ARID1A.
Main Results:
- Identified peptidic ligands with nanomolar affinity for ARID1B.
- Demonstrated high selectivity of these peptides for ARID1B over ARID1A.
- Characterized peptide binding to two distinct pockets, including an ARID1B-exclusive cysteine.
Conclusions:
- ARID1B is a 'ligandable' target, validated by selective peptide binders.
- The identified peptides serve as valuable tools for drug discovery.
- Findings suggest opportunities for developing selective molecules targeting ARID1B for cancer therapy.
