Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.
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Abstract | :
p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability. |
Year of Publication | :
2018
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Journal | :
ACS medicinal chemistry letters
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Volume | :
9
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Issue | :
1
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Number of Pages | :
28-33
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Date Published | :
2018
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DOI | :
10.1021/acsmedchemlett.7b00395
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Short Title | :
ACS Med Chem Lett
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