Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex

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• 作者：Charlotte L. Sutherell ; Cynthia Tallant ; Octovia P. Monteiro ; Clarence Yapp ; Julian E. Fuchs ; Oleg Fedorov ; Paulina Siejka ; Suzanne Müller ; Stefan Knapp ; James D. Brenton ; Paul E. Brennan ; Steven V. Ley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：5095-5101
• 全文大小：516K
• 年卷期：0
• ISSN：1520-4804

文摘

Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a K_D of 124 nM, SMARCA2B and SMARCA4 with K_D values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.