Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Dec 7;7(12):2246-2264.
doi: 10.1039/c6md00373g. Epub 2016 Sep 7.

Chemical probes and inhibitors of bromodomains outside the BET family

Moses Moustakim  1   2   3 , Peter G K Clark  4 , Duncan A Hay  5 , Darren J Dixon  1 , Paul E Brennan  2   3
Affiliations
Review

Chemical probes and inhibitors of bromodomains outside the BET family

Moses Moustakim et al. Medchemcomm. .

Abstract

In the last five years, the development of inhibitors of bromodomains has emerged as an area of intensive worldwide research. Emerging evidence has implicated a number of non-BET bromodomains in the onset and progression of diseases such as cancer, HIV infection and inflammation. The development and use of small molecule chemical probes has been fundamental to pre-clinical evaluation of bromodomains as _targets. Recent efforts are described highlighting the development of potent, selective and cell active non-BET bromodomain inhibitors and their therapeutic potential. Over half of typical bromodomains now have reported ligands, but those with atypical binding site residues remain resistant to chemical probe discovery efforts.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Bromodomains with reported inhibitors. A. Brd inhibitors such as LP99 (pale ball and stick) bind in the acetyl lysine binding pocket (green ribbon) to a common Asn residue (green ball and stick) and a network of water molecules (blue CPK) (LP99 and BRD9 from PDB ID 5IGN). B. Distribution of acetyl lysine binding residues in Brd pockets. Brds are colored by their acetyl lysine binding residue (red: Asn, blue: Tyr, green: Thr, purple: Asp). All reported Brd inhibitors (grey sections of bars) _target Brds with a typical Asn residue with the exception of PHIP(2) which has a Thr. C. Brds in grey boxes have reported inhibitors. Brds in colored typeface have no reported inhibitors (colors as in B).
Fig. 2
Fig. 2. PCAF bromodomain inhibitors.
Fig. 3
Fig. 3. CECR2/BPTF inhibitors.
Fig. 4
Fig. 4. Early CBP inhibitors from the Zhou group.
Fig. 5
Fig. 5. Dihydroquinoxalinone CBP inhibitors.
Fig. 6
Fig. 6. Isoxazole and related CBP/p300 inhibitors.
Fig. 7
Fig. 7. CBP/p300 chemical probe I-CBP112.
Fig. 8
Fig. 8. CBP inhibitors from Nevado and Caflisch.
Fig. 9
Fig. 9. Optimized CBP inhibitor from Nevado and Caflisch.
Fig. 10
Fig. 10. CBP/p300 inhibitors from Constellation and Genentech.
Fig. 11
Fig. 11. PHIP(2) fragment hits.
Fig. 12
Fig. 12. BRD7 and BRD9 inhibitors.
Fig. 13
Fig. 13. BRPF1B inhibitors.
Fig. 14
Fig. 14. ATAD2 inhibitors.
Fig. 15
Fig. 15. BAZ2A/BAZ2B inhibitors.
Fig. 16
Fig. 16. Dual TRIM24/BRPF1 inhibitors.
Fig. 17
Fig. 17. TAF1(2) inhibitor compound 40 sub-family VIII.
Fig. 18
Fig. 18. PB1/SMARCA2/SMARCA4 inhibitors.
None
Moses Moustakim
None
Peter G. K. Clark
None
Duncan Hay
None
Darren J. Dixon
None
Paul E. Brennan
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Arrowsmith C. H., Bountra C., Fish P. V., Lee K., Schapira M. Nat. Rev. Drug Discovery. 2012;11:384–400. - PubMed
    1. Esteller M. N. Engl. J. Med. 2008;358:1148–1159. - PubMed
    1. Jones P. A., Laird P. W. Nat. Genet. 1999;21:163–167. - PubMed
    1. Dawson M. A., Kouzarides T., Huntly B. J. P. N. Engl. J. Med. 2012;367:647–657. - PubMed
    1. Shanmugam M. K., Sethi G. Subcell. Biochem. 2013;61:627–657. - PubMed
  NODES
innovation 2
twitter 2