Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors
| Autor: | Rab K. Prinjha, Emmanuel Hubert Demont, Rebecca C. Furze, Chun-wa Chung, Robert J. Sheppard, Robert J. Watson, Heather A. Barnett, Christina Rau, Paul Bamborough, Anne-Marie Michon, Thilo Werner, Paola Grandi, Darren Jason Mitchell |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation Druggability Chemical probe Cell Cycle Proteins Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Protein Domains Drug Discovery Humans Molecular Structure Nuclear Proteins Tropane Combinatorial chemistry Bromodomain DNA-Binding Proteins 030104 developmental biology chemistry 030220 oncology & carcinogenesis Molecular Medicine ATPases Associated with Diverse Cellular Activities Piperidine Selectivity Transcription Factors |
| Zdroj: | Journal of medicinal chemistry. 61(18) |
| ISSN: | 1520-4804 |
| Popis: | ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family. |
| Databáze: | OpenAIRE |
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