166735-12-2Relevant articles and documents
Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases
Michaelides, Michael R.,Kluge, Arthur,Patane, Michael,Van Drie, John H.,Wang, Ce,Hansen, T. Matthew,Risi, Roberto M.,Mantei, Robert,Hertel, Carmen,Karukurichi, Kannan,Nesterov, Alexandre,McElligott, David,De Vries, Peter,Langston, J. William,Cole, Philip A.,Marmorstein, Ronen,Liu, Hong,Lasko, Loren,Bromberg, Kenneth D.,Lai, Albert,Kesicki, Edward A.
supporting information, p. 28 - 33 (2018/05/04)
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.
SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
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Page/Page column 541, (2016/04/10)
Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
