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Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases

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journal contribution
posted on 13.12.2017, 00:00 by Michael R. Michaelides, Arthur Kluge, Michael Patane, John H. Van Drie, Ce Wang, T. Matthew Hansen, Roberto M. Risi, Robert Mantei, Carmen Hertel, Kannan Karukurichi, Alexandre Nesterov, David McElligott, Peter de Vries, J. William Langston, Philip A. Cole, Ronen Marmorstein, Hong Liu, Loren Lasko, Kenneth D. Bromberg, Albert Lai, Edward A. Kesicki
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.