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Review
. 2018 Aug 7;9(11):1779-1802.
doi: 10.1039/c8md00198g. eCollection 2018 Nov 1.

Targeting Brd4 for cancer therapy: inhibitors and degraders

Affiliations
Review

Targeting Brd4 for cancer therapy: inhibitors and degraders

Yingchao Duan et al. Medchemcomm. .

Abstract

Bromodomain-containing protein 4 (Brd4) plays an important role in mediating the expression of genes involved in cancers and non-cancer diseases such as inflammatory diseases and acute heart failure. Inactivating Brd4 or downregulating its expression inhibits cancer development, leading to the current interest in Brd4 as a promising anticancer drug target. Numerous Brd4 inhibitors have been studied in recent years and some of them are currently in various phases of clinical trials. Recently, selective degradation of target proteins by small bifunctional molecules (PROTACs) has emerged as an attractive drug discovery approach owing to the advantages it could offer over traditional small-molecule inhibitors. A number of Brd4 degraders have been reported and showed more efficient anticancer activities than just protein inhibition. In this review, we will discuss recent findings in the discovery and development of small-molecule inhibitors and degraders that target Brd4 as a potential anticancer agent.

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Figures

Fig. 1
Fig. 1. Reported thienotriazolodiazepine-based Brd4 inhibitors.
Fig. 2
Fig. 2. Discovery and development of Brd4 inhibitor I-BET762.
Fig. 3
Fig. 3. Chemical structures of compounds 11–15.
Fig. 4
Fig. 4. Discovery and development of Brd4 inhibitor CPI-0610.
Fig. 5
Fig. 5. Chemical structures of compounds 20–25.
Fig. 6
Fig. 6. Reported isoxazole-based Brd4 inhibitors.
Fig. 7
Fig. 7. Reported benzo[d]isoxazole-based Brd4 inhibitors.
Fig. 8
Fig. 8. Reported pyridone-based Brd4 inhibitors.
Fig. 9
Fig. 9. Reported fused polycyclic pyridone-based Brd4 inhibitors.
Fig. 10
Fig. 10. Reported tetrahydroquinoline-based Brd4 inhibitors.
Fig. 11
Fig. 11. Reported triazolopyrazine-based Brd4 inhibitors.
Fig. 12
Fig. 12. Reported 4-acyl pyrrole-based Brd4 inhibitors.
Fig. 13
Fig. 13. Reported 2-thiazolidinone-based Brd4 inhibitors.
Fig. 14
Fig. 14. Other reported Brd4 inhibitors.
Fig. 15
Fig. 15. Discovery and development of bivalent Brd4 inhibitor 89.
Fig. 16
Fig. 16. Binding modes for bivalent Brd4 inhibitor 88.
Fig. 17
Fig. 17. The structure of bivalent Brd4 inhibitor MT1.
Fig. 18
Fig. 18. Mechanism of protein degradation by PROTACs.
Fig. 19
Fig. 19. Reported CRL4CRBN E3 and CRL2VHL E3 small-molecule ligands.
Fig. 20
Fig. 20. Mechanism of Brd4 degradation by CRL4CRBN E3-based Brd4 degraders.
Fig. 21
Fig. 21. Reported Brd4 degraders based on CRL4CRBN E3 ligase.
Fig. 22
Fig. 22. Mechanism of Brd4 degradation by CRL2VHL E3-based Brd4 degraders.
Fig. 23
Fig. 23. Reported Brd4 degraders based on CRL2VHL E3 ligase.

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