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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Peer-reviewed
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Type
Article
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Authors
Sutherell, Charlotte L
Tallant, Cynthia
Monteiro, Octovia P
Yapp, Clarence
Fuchs, Julian E
Abstract
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 KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.
Description
Keywords
DNA Helicases, DNA-Binding Proteins, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Nuclear Proteins, Pyrroles, Quinazolinones, Structure-Activity Relationship, Transcription Factors
Journal Title
J Med Chem
Conference Name
Journal ISSN
0022-2623
1520-4804
1520-4804
Volume Title
59
Publisher
American Chemical Society (ACS)
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Sponsorship
Engineering and Physical Sciences Research Council (EP/K009494/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Cancer Research UK (22905)
Cancer Research UK (15601)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Cancer Research UK (22905)
Cancer Research UK (15601)
C.L.S. was funded by the Cambridge Ph.D. Training Programme in Chemical Biology and Molecular Medicine. We gratefully acknowledge the EPSRC (SVL, Grants EP/K099494/1 and EP/K039520/1). The SGC is a registered charity (No. 1097737) that received funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development, and Innovation, Pfizer, Takeda, and the Wellcome Trust (Grant 092809/Z/10/Z).