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Updated: Aug 14, 2026
10:05
Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC (Crosslinking of Small Molecules to Isolate Chromatin)
Published on: January 20, 2016
Cryptic small-molecule binding sites in the ARID1B DNA-binding domain
Christine E Carbone1, Heike Schönherr1, Victor Y Zhao1
1Relay Therapeutics Inc., Cambridge, MA 02139.
Summary
Targeting ARID1B offers a synthetic lethality strategy for ARID1A-mutant cancers. Researchers identified novel compounds binding to cryptic pockets in ARID1B, enabling selective ARID1B targeting for precision cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- ARID1A mutations are common in human cancers.
- ARID1B depletion shows synthetic lethality with ARID1A mutations.
- ARID1B lacks a druggable pocket, hindering targeted therapy.
Purpose of the Study:
- To investigate ARID1B's druggability for ARID1A-mutant cancers.
- To identify small molecules that selectively bind ARID1B.
- To explore ARID1B's conformational dynamics for therapeutic targeting.
Main Methods:
- Molecular dynamics simulations of ARID1B's AT-rich Interaction Domain (ARID).
- 2D protein-detected NMR fragment screening.
- X-ray crystallography of ARID1B ARID-compound complexes.
Main Results:
- ARID1B ARID exhibits conformational dynamics exposing ligandable sites.
- Two compounds identified that bind ARID1B ARID with slow kinetics.
- X-ray structures reveal compounds bind distinct cryptic pockets in ARID1B.
- Selective binding to ARID1B over ARID1A demonstrated (up to 140-fold).
Conclusions:
- ARID1B's cryptic pockets are druggable targets.
- Identified compounds provide a basis for selective ARID1B-targeted therapies.
- This approach enables precision targeting of ARID1A-mutant cancers.
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