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A Chemical Probe for the ATAD2 Bromodomain
Paul Bamborough1, Chun-Wa Chung2, Emmanuel H Demont3
1GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. Paul.A.Bamborough@gsk.com.
Angewandte Chemie (International Ed. in English)
|August 18, 2016
Summary
Researchers developed a new chemical probe targeting the ATAD2 protein, a challenge in cancer research. This probe is highly selective, cell-permeable, and effective at low nanomolar concentrations, offering a promising tool for cancer studies.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Oncology
Background:
- The ATAD2 protein is implicated in cancer development.
- The ATAD2 bromodomain presents significant challenges for drug development.
- Existing chemical probes for ATAD2 lack optimal properties.
Purpose of the Study:
- To design and synthesize a novel, potent, and selective chemical probe for ATAD2.
- To overcome the 'undruggable' nature of the ATAD2 bromodomain.
- To create a cell-permeable probe for studying ATAD2 in biological systems.
Main Methods:
- Utilized a potent lead compound for optimization.
- Employed a dual approach involving CF2 as a sulfone bio-isostere.
- Incorporated 1,3-interactions to control piperidine ring conformation.
Main Results:
- Achieved low-nanomolar potency against ATAD2.
- Enhanced probe selectivity for the ATAD2 target.
- Confirmed cell permeability of the developed chemical probe.
- The first selective and cell-permeable chemical probe for ATAD2 was reported.
Conclusions:
- The novel chemical probe represents a significant advancement in ATAD2-targeted research.
- This probe facilitates further investigation into ATAD2's role in cancer.
- The synthetic strategies employed offer a blueprint for targeting challenging protein domains.
