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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.


(a) Cocrystalstructure of 28 with PB1(5) at 1.6 Å(PDB code 5FH8). (b) Overlay of PDB code 5FH7 (gray) of 18 and PDB code 5FH8 (cyan) of 28 showing the shift in the ZA loop of the PB1(5) domain onbinding of 28.
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fig5: (a) Cocrystalstructure of 28 with PB1(5) at 1.6 Å(PDB code 5FH8). (b) Overlay of PDB code 5FH7 (gray) of 18 and PDB code 5FH8 (cyan) of 28 showing the shift in the ZA loop of the PB1(5) domain onbinding of 28.

Mentions: Understanding the reason for the change in affinity would helpdesign of future chemical probes with selectivity for bromodomainsnot yet targeted such as PB1(2–4) and offers the intriguingpossibility of targeting PB1 selectively over SMARCA2/4. We obtaineda cocrystal structure of 28 with PB1(5) (Figure 5) to understand its uniquefeatures. This revealed a shift in the ZA loop region of PB1(5), makingthe KAc pocket wider and increasing its similarity to the PB1(2) KAcpocket. The ethyl side chains interact with the hydrophobic edgesof the pocket and begin to occupy the ill-defined peptide-bindingchannel in PB1(5). Although no structure was obtained to confirm this,we propose that in SMARCA4, Ile1543 blocks this channel, preventingthe ethyl side chains from being accommodated in the smaller pocket.


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)

(a) Cocrystalstructure of 28 with PB1(5) at 1.6 Å(PDB code 5FH8). (b) Overlay of PDB code 5FH7 (gray) of 18 and PDB code 5FH8 (cyan) of 28 showing the shift in the ZA loop of the PB1(5) domain onbinding of 28.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: (a) Cocrystalstructure of 28 with PB1(5) at 1.6 Å(PDB code 5FH8). (b) Overlay of PDB code 5FH7 (gray) of 18 and PDB code 5FH8 (cyan) of 28 showing the shift in the ZA loop of the PB1(5) domain onbinding of 28.
Mentions: Understanding the reason for the change in affinity would helpdesign of future chemical probes with selectivity for bromodomainsnot yet targeted such as PB1(2–4) and offers the intriguingpossibility of targeting PB1 selectively over SMARCA2/4. We obtaineda cocrystal structure of 28 with PB1(5) (Figure 5) to understand its uniquefeatures. This revealed a shift in the ZA loop region of PB1(5), makingthe KAc pocket wider and increasing its similarity to the PB1(2) KAcpocket. The ethyl side chains interact with the hydrophobic edgesof the pocket and begin to occupy the ill-defined peptide-bindingchannel in PB1(5). Although no structure was obtained to confirm this,we propose that in SMARCA4, Ile1543 blocks this channel, preventingthe ethyl side chains from being accommodated in the smaller pocket.

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.