A Chemical Probe for the ATAD2 Bromodomain.

Paul Bamborough,Chun-wa Chung,Emmanuel Demont,Rebecca C. Furze,Andrew J. Bannister,Ka Hing Che,Hawa Diallo,Clement Douault,Paola Grandi,Tony Kouzarides,Anne-Marie Michon,Darren Jason Mitchell,Rab K. Prinjha,Christina Rau,Samuel Robson,Robert J. Sheppard,Richard J. Upton,Robert J. Watson

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION（2016）

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摘要

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.

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关键词

bioisosteres,conformation analysis,epigenetics,fluorine,medicinal chemistry

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