Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex.
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.
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.|Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, U.K.
Charlotte L
CL
Sutherell
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
Cynthia
C
Tallant
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
Octovia P
OP
Monteiro
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
Clarence
C
Yapp
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
Julian E
JE
Fuchs
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
Oleg
O
Fedorov
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
Paulina
P
Siejka
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
Suzanne
S
Müller
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.|Department of Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Goethe University Frankfurt , 60438 Frankfurt am Main, Germany.
Stefan
S
Knapp
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, CB2 0RE, U.K.
James D
JD
Brenton
The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.|Target Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Headington, Oxford OX3 7FZ, U.K.
Paul E
PE
Brennan
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
Steven V
SV
Ley
D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
C000619434:6-chloro-3-((4-methylpiperazin-1-yl)methylene)-2,3-dihydropyrrolo(1,2-a)quinazolin-5(1H)-one; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D011758:Pyrroles; D052999:Quinazolinones; C084011:SMARCA2 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases