Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery

Abstract

As a conserved protein interaction module that recognizes and binds to acetylated lysine, bromodomain (BRD) contains a deep, largely hydrophobic acetyl lysine binding site. Proteins that share the feature of containing two BRDs and an extra-terminal domain belong to BET family, including BRD2, BRD3, BRD4 and BRDT. BET family proteins perform transcription regulatory function under normal conditions, while in cancer, they regulate transcription of several oncogenes, such as c-Myc and Bcl-2. Thus, targeting BET proteins may be a promising strategy, and intense interest of BET proteins has fueled the development of structure-based bromodomain inhibitors in cancer. In this review, we focus on summarizing several small-molecule BET inhibitors and their relevant anti-tumor mechanisms, which would provide a clue for exploiting new targeted BET inhibitors in the future cancer therapy.

Keywords: BET inhibitor; BRD2/4; BRD3; BRDT; bromodomain.

Figure 1. Molecular structures of BET bromodomains

Crucial post-translational modification sites and main features of BET proteins. (B) Structure of BET proteins.

Figure 2. Biological function of BET bromodomains

Through sharing the highly similarity of amino acids sequences and all function as protein scaffolds, BRD2, BRD3 and BRD4 recruit different proteins. (A) BRD4 recruits proteins in a PTEFb-dependent manner, and it regulates the transcription process through coupling with RNA P II. (B) (C) BRD2 and BRD3 both exert function through E2F-RB pathway and in a PTEFb-independent manner, while BRD2 distinct from BRD3 for its ability to binding with SWI/SNF complex and regulating binding of ATP and histones. (D) The process how HDAC inhibits transcription through binding with BRD2 and E2F-Rb complex. (E) The process how BRD4 regulate transcription.

Figure 3. BRD2/4 inhibitors and their relevant anti-cancer pathways

Inhibitors of BRD2 and BRD4 have been detected to exert the anti-cancer ability in leukemia, lymphoma, NMC and other tumors. (A) In leukemia, inhibiting BRD4 to regulate transcription of c-Myc can effectively suppress the cell growth. (B) (C) In lymphoma and other solid tumors, inhibiting of BRD2/4 can lead to low expression of specific oncogenes, making BET inhibitors attractive anti-cancer agents. (D) In NMC, suppression of BRD4 can inhibit emerging of BRD4-NUT fusion proteins.

Figure 4. BRD3 and BRDT inhibitors and their relevant anti-cancer pathways

(A) Fused with NUT gene, BRD3 may encode BRD3-NUT fusion proteins in NMC, which is similar with BRD4. Specifically inhibiting BRD3-NUT fusion protein can block BRD3-NUT gene transcription, and inhibit NMC cell growth. (B) Pan-inhibitors I-BET762 and JQ1 inhibits BRD3. (C) As the only member of BET family can bind with transcription factor GATA1, inhibition of BRD3 through BRD3-GATA pathway by clinical experimental compound, RVX-208, may be a therapeutic strategy in hepatocellular carcinoma. (D) The least known BET family member, BRDT, is also been detected the anti-cancer capacity in leukemia by an unspecific-target drug Dinaciclib.