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

Sutherell CL, Tallant C, Monteiro OP, Yapp C, Fuchs JE, Fedorov O, Siejka P, Müller S, Knapp S, Brenton JD, Brennan PE, Ley SV - J. Med. Chem. (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.

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.

No MeSH data available.


Related in: MedlinePlus

RepresentativeITC trace, measured using 26 and thebromodomain of PB1(5); 30 consecutive injections of PB1(5) into asolution of 26 in 20 mM HEPES, 150 mM NaCl, 0.05 mM TCEP.Raw heats (left) and normalized injection heats with a nonlinear least-squaresfit for a single binding site model (right) are shown.
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fig4: RepresentativeITC trace, measured using 26 and thebromodomain of PB1(5); 30 consecutive injections of PB1(5) into asolution of 26 in 20 mM HEPES, 150 mM NaCl, 0.05 mM TCEP.Raw heats (left) and normalized injection heats with a nonlinear least-squaresfit for a single binding site model (right) are shown.

Mentions: In our screening, compounds appeared to interact with the bromodomainsin both SMARCA2 isoforms, A and B, and in SMARCA4 and PB1(5). ITCwas used to further assess the binding of 26 (Figure 4) to SMARCA2B andSMARCA4, giving KD values of 262 and 417nM, respectively. Binding to the SMARCA bromodomains had not beenobserved prior to inclusion of the chlorine substitution, suggestingthat the proposed halogen bond is again important for binding.


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

Sutherell CL, Tallant C, Monteiro OP, Yapp C, Fuchs JE, Fedorov O, Siejka P, Müller S, Knapp S, Brenton JD, Brennan PE, Ley SV - J. Med. Chem. (2016)

RepresentativeITC trace, measured using 26 and thebromodomain of PB1(5); 30 consecutive injections of PB1(5) into asolution of 26 in 20 mM HEPES, 150 mM NaCl, 0.05 mM TCEP.Raw heats (left) and normalized injection heats with a nonlinear least-squaresfit for a single binding site model (right) are shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920105&req=5

fig4: RepresentativeITC trace, measured using 26 and thebromodomain of PB1(5); 30 consecutive injections of PB1(5) into asolution of 26 in 20 mM HEPES, 150 mM NaCl, 0.05 mM TCEP.Raw heats (left) and normalized injection heats with a nonlinear least-squaresfit for a single binding site model (right) are shown.
Mentions: In our screening, compounds appeared to interact with the bromodomainsin both SMARCA2 isoforms, A and B, and in SMARCA4 and PB1(5). ITCwas used to further assess the binding of 26 (Figure 4) to SMARCA2B andSMARCA4, giving KD values of 262 and 417nM, respectively. Binding to the SMARCA bromodomains had not beenobserved prior to inclusion of the chlorine substitution, suggestingthat the proposed halogen bond is again important for binding.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.

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.

No MeSH data available.


Related in: MedlinePlus