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In Silico Design, Chemical Synthesis, Biophysical and in Vitro Evaluation for the Identification of 1‐Ethyl‐1H‐Pyrazolo[3,4‐b]Pyridine‐Based BRD9 Binders.
- Source :
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ChemPlusChem . Aug2024, p1. 14p. 7 Illustrations. - Publication Year :
- 2024
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Abstract
- In this work, we report the identification of novel bromodomain‐containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure‐based pharmacophore model. The <italic>in silico</italic> workflow here described led to the identification of a promising initial hit (<bold>1</bold>) featuring the 1‐ethyl‐1<italic>H</italic>‐pyrazolo[3,4‐<italic>b</italic>]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound <bold>1</bold> prompted us to explore further tailored structural modification around the C‐4 and C‐6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives (<bold>2</bold>–<bold>20</bold>) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds (<bold>5</bold>, <bold>11</bold>, <bold>12</bold>, and <bold>19</bold>) stood out in biophysical assays as new valuable BRD9 ligands featuring IC50 values in the low‐micromolar range. Noteworthy, a promising antiproliferative activity was detected <italic>in vitro</italic> for compound <bold>5</bold> on HeLa and A375 cancer cell line. The successful combination and application of <italic>in silico</italic> tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target. [ABSTRACT FROM AUTHOR]
- Subjects :
- *DRUG discovery
*BIOLOGICAL assay
*CHEMICAL synthesis
*BINDING sites
*PHARMACOPHORE
Subjects
Details
- Language :
- English
- ISSN :
- 21926506
- Database :
- Academic Search Index
- Journal :
- ChemPlusChem
- Publication Type :
- Academic Journal
- Accession number :
- 180316791
- Full Text :
- https://doi.org/10.1002/cplu.202400339