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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.


Cocrystal structure of 18 with PB1(5) at 1.5 Å(PDB code 5FH7): (a) cut-through illustrating positioning of chlorine in cavity;(b) surface view illustrating fit in PB1(5) pocket.
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fig3: Cocrystal structure of 18 with PB1(5) at 1.5 Å(PDB code 5FH7): (a) cut-through illustrating positioning of chlorine in cavity;(b) surface view illustrating fit in PB1(5) pocket.

Mentions: This interactionwas confirmed by a cocrystal structure of 18 with PB1(5),in which the chlorine occupies the cavitypreviously observed with a separation of 3.2 Å from the carbonyloxygen of Met731. This is consistent with a halogen bond (Figure 3).30 A slight twist in the scaffold, to maximize interactionswith both Tyr696 and Asn739, can be observed. Comparison with PFI-3shows that the interaction with Met731 has not been previously exploited(Supporting Information).


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)

Cocrystal structure of 18 with PB1(5) at 1.5 Å(PDB code 5FH7): (a) cut-through illustrating positioning of chlorine in cavity;(b) surface view illustrating fit in PB1(5) pocket.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Cocrystal structure of 18 with PB1(5) at 1.5 Å(PDB code 5FH7): (a) cut-through illustrating positioning of chlorine in cavity;(b) surface view illustrating fit in PB1(5) pocket.
Mentions: This interactionwas confirmed by a cocrystal structure of 18 with PB1(5),in which the chlorine occupies the cavitypreviously observed with a separation of 3.2 Å from the carbonyloxygen of Met731. This is consistent with a halogen bond (Figure 3).30 A slight twist in the scaffold, to maximize interactionswith both Tyr696 and Asn739, can be observed. Comparison with PFI-3shows that the interaction with Met731 has not been previously exploited(Supporting Information).

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.