Related Experiment Video
Updated: Jun 4, 2026
In Vitro Chemical Mapping of G-Quadruplex DNA Structures by Bis-3-Chloropiperidines
Published on: May 12, 2023
Unusual backfolded binding poses of BAZ2A bromodomain binders
Andrea Dalle Vedove1, Giulia Cazzanelli1, Vito Giuseppe D'Agostino1
1Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Via Sommarive 9, 38123 Povo - Trento, Italy.
Abstract:
BAZ2A is a large multidomain protein overexpressed in aggressive prostate cancer, where it potentiates migration and invasion of other tissues. To counteract its metastasis-promoting role, small molecules interfering with the recognition of acetylated lysines by the BAZ2A bromodomain have been identified. However, unlike other bromodomains, BAZ2A has a shallow pocket, which significantly complicates the development of potent inhibitors. Here, we report the exploration of the acetyl-pyrrole scaffold, leading to the identification of BAZ2A-binding compounds assuming a peculiar, almost enclosed, conformation, as determined by X-ray crystallography. These molecules pose the basis for the development of potent BAZ2A macrocyclic inhibitors, as performed for other bromodomains.
Insights
Researchers explored novel compounds targeting the BAZ2A protein, crucial in prostate cancer metastasis. They identified unique BAZ2A-binding molecules, paving the way for developing potent inhibitors against this challenging cancer target.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- The BAZ2A protein is overexpressed in aggressive prostate cancer, promoting tumor cell migration and invasion.
- Targeting the BAZ2A bromodomain with small molecules is a strategy to inhibit its metastasis-promoting role.
- BAZ2A's shallow binding pocket presents a significant challenge for developing potent inhibitors.
Purpose of the Study:
- To explore novel chemical scaffolds for inhibiting BAZ2A.
- To identify compounds that bind to the BAZ2A bromodomain despite its challenging pocket.
- To lay the groundwork for developing potent BAZ2A macrocyclic inhibitors.
Main Methods:
- Exploration of the acetyl-pyrrole scaffold.
- Identification of BAZ2A-binding compounds.
- X-ray crystallography to determine compound conformation.
Main Results:
- Novel BAZ2A-binding compounds were identified using the acetyl-pyrrole scaffold.
- These compounds adopt a unique, enclosed conformation within the BAZ2A binding site.
- The findings provide a basis for designing potent BAZ2A inhibitors.
Conclusions:
- The acetyl-pyrrole scaffold is a promising starting point for BAZ2A inhibitor development.
- The identified compounds' unique conformation offers new insights into targeting shallow bromodomain pockets.
- This research advances the development of therapeutics for metastatic prostate cancer.
Related Concept Videos
01:49Conserved Binding Sites
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
01:49Conserved Binding Sites
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
02:13Cooperative Binding of Transcription Regulators
02:13Cooperative Binding of Transcription Regulators
02:21Globular and Fibrous Proteins
Globular proteins are also known as spheroproteins and typically are approximately round in shape. They contain a mix of amino acid types and contain differing sequences in their primary structures. Globular proteins have many different functions, such as enzymes, cellular messengers, and molecular transporters. These roles often require the proteins to be...
02:18The Equilibrium Binding Constant and Binding Strength