Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex
Sutherell, Charlotte L
Monteiro, Octovia P
Fuchs, Julian E
Brennan, Paul E
Journal of Medicinal Chemistry
American Chemical Society
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Sutherell, C. L., Tallant, C., Monteiro, O. P., Yapp, C., Fuchs, J. E., Fedorov, O., Siejka, P., et al. (2016). Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex. Journal of Medicinal Chemistry, 59 5095-5101. https://doi.org/10.1021/acs.jmedchem.5b01997
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.
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).
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External DOI: https://doi.org/10.1021/acs.jmedchem.5b01997
This record's URL: https://www.repository.cam.ac.uk/handle/1810/256045