Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases
| Autor: | David L. McElligott, Albert Lai, Alexandre Nesterov, Robert A. Mantei, T. Matthew Hansen, Peter de Vries, Arthur F. Kluge, Ronen Marmorstein, Michael R. Michaelides, Hong Liu, Kesicki Edward A, Kannan R. Karukurichi, J. William Langston, John H. Van Drie, Loren M. Lasko, Carmen Hertel, Michael A. Patane, Kenneth D. Bromberg, Ce Wang, Philip A. Cole, Roberto M. Risi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Letter Hydantoin p300 CBP 01 natural sciences Biochemistry 03 medical and health sciences chemistry.chemical_compound Drug Discovery Histone Acetyltransferases Regulation of gene expression Oxazolidinedione biology 010405 organic chemistry Organic Chemistry Histone acetyltransferase Ligand (biochemistry) 0104 chemical sciences 030104 developmental biology Histone chemistry Acetylation biology.protein histone acetyl transferase |
| Zdroj: | ACS Medicinal Chemistry Letters |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.7b00395 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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