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

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

  • J Med Chem. 2016 May 26;59(10):5095-101. doi: 10.1021/acs.jmedchem.5b01997.
Charlotte L Sutherell 1 2,  Cynthia Tallant 3 4,  Octovia P Monteiro 3 4,  Clarence Yapp 3 4,  Julian E Fuchs 1,  Oleg Fedorov 3 4,  Paulina Siejka 3 4,  Suzanne Müller 3 4,  Stefan Knapp 3 4 5,  James D Brenton 2,  Paul E Brennan 3 4,  Steven V Ley 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
  • 2 Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, U.K.
  • 3 The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.
  • 4 Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
  • 5 Department of Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University Frankfurt , 60438 Frankfurt am Main, Germany.
PMID: 27119626 DOI: 10.1021/acs.jmedchem.5b01997
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.

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