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Published on: May 16, 2021
Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors
Emmanuel H Demont, Chun-wa Chung, Rebecca C Furze
1§Molecular Discovery Research, Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Abstract:
Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.
Insights
Researchers discovered new micromolar inhibitors for the ATAD2 bromodomain, a key target in cancer progression. This breakthrough advances understanding of ATAD2's role in cancer and opens avenues for potential therapies.
Area of Science:
- Oncology
- Chemical Biology
- Molecular Biology
Background:
- Overexpression of ATAD2 (ATPase family, AAA domain containing 2) is associated with cancer severity and progression.
- ATAD2's role in regulating cancer growth drivers is established, but its bromodomain function is poorly understood.
- The lack of selective ATAD2 bromodomain inhibitors hinders therapeutic development.
Purpose of the Study:
- To discover and optimize inhibitors targeting the ATAD2 bromodomain.
- To explore the therapeutic potential of targeting the ATAD2 bromodomain in cancer.
Main Methods:
- Fragment-based drug discovery approach.
- Targeted array screening.
- Chemical optimization of initial hits.
Main Results:
- Identification of a novel hit compound from a fragment-based screen.
- Optimization yielded the first known micromolar inhibitors of the ATAD2 bromodomain.
- These inhibitors provide tools to study ATAD2 bromodomain function.
Conclusions:
- The developed inhibitors represent a significant advancement in ATAD2 bromodomain research.
- These compounds can facilitate further investigation into ATAD2's role in cancer.
- This work lays the foundation for developing novel cancer therapeutics targeting ATAD2.
