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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.


Selectivity of 26. Inhibitor 26 was screenedat 10 μM against selected bromodomains by DSF assay. Temperatureshifts for screened proteins are shown on the phylogenetic tree.
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fig6: Selectivity of 26. Inhibitor 26 was screenedat 10 μM against selected bromodomains by DSF assay. Temperatureshifts for screened proteins are shown on the phylogenetic tree.

Mentions: We assessed the selectivity of the most potent pan-PB1, SMARCA2/4analogue 26 against representative bromodomains (PCAF,BRD4(1), CREBBP, TRIM33B) from other subfamilies using DSF (Figure 6). No significantbinding was observed.


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)

Selectivity of 26. Inhibitor 26 was screenedat 10 μM against selected bromodomains by DSF assay. Temperatureshifts for screened proteins are shown on the phylogenetic tree.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Selectivity of 26. Inhibitor 26 was screenedat 10 μM against selected bromodomains by DSF assay. Temperatureshifts for screened proteins are shown on the phylogenetic tree.
Mentions: We assessed the selectivity of the most potent pan-PB1, SMARCA2/4analogue 26 against representative bromodomains (PCAF,BRD4(1), CREBBP, TRIM33B) from other subfamilies using DSF (Figure 6). No significantbinding was observed.

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.