Lysine acetylation is a protein post-translational modification which effect the relaxing of the chromatin structure, making chromosomal DNA more accessible. Among the different enzymes responsible for this transformation (KATs), p300 is one of the most studied: the dysregulation of its activity leads to many human diseases. Nevertheless, a limited number of p300 modulators have been described so far: one of the main problem is the absence of a gold standard screening technique for this enzyme because of the intrinsic limitation of each method. We decided to develop a robust and widely usable combined screening platform to identify small molecule modulators of p300, using different biophysical and biomolecular techniques to interrogate the target and to validate the outputs. The multiple platform was applied to two different libraries of small molecule compounds, derived from the molecular pruning of anacardic acid and garcinol, natural inhibitors of p300. This combined approach allowed us to identify and deeply characterize the activity of new chemical probes, very useful for the study of p300-mediated lysine acetylation and its implications in physiological and/or pathological processes.

Biomolecular and biophysical approaches to interrogate p300: a platform for drug discovery.

Feoli, Alessandra;Milite, Ciro;Tosco, Alessandra;Castellano, Sabrina;Sbardella, Gianluca
2015-01-01

Abstract

Lysine acetylation is a protein post-translational modification which effect the relaxing of the chromatin structure, making chromosomal DNA more accessible. Among the different enzymes responsible for this transformation (KATs), p300 is one of the most studied: the dysregulation of its activity leads to many human diseases. Nevertheless, a limited number of p300 modulators have been described so far: one of the main problem is the absence of a gold standard screening technique for this enzyme because of the intrinsic limitation of each method. We decided to develop a robust and widely usable combined screening platform to identify small molecule modulators of p300, using different biophysical and biomolecular techniques to interrogate the target and to validate the outputs. The multiple platform was applied to two different libraries of small molecule compounds, derived from the molecular pruning of anacardic acid and garcinol, natural inhibitors of p300. This combined approach allowed us to identify and deeply characterize the activity of new chemical probes, very useful for the study of p300-mediated lysine acetylation and its implications in physiological and/or pathological processes.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4719092
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