Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Abstract

Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones and nonhistone proteins via tandem bromodomains and regulate chromatin dynamics, cellular processes, and disease procession. Thus targeting BET proteins is a promising strategy for treating various diseases, especially malignant tumors and chronic inflammation. Many pan-BET small-molecule inhibitors have been described, and some of them are in clinical evaluation. Nevertheless, the limited clinical efficacy of the current BET inhibitors is also evident and has inspired the development of new technologies to improve their clinical outcomes and minimize unwanted side effects. In this Review, we summarize the latest protein characteristics and biological functions of BRD4 as an example of BET proteins, analyze the clinical development status and preclinical resistance mechanisms, and discuss recent advances in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis targeting chimera degraders, and protein-protein interaction inhibitors.

Figure 1.

(A) Domain organization of human BET proteins. (B) Conserved sequence of BRD4 BD1 and BRD4 BD2. Key varying residues are marked in different colors. (C) Recruitment of P-TEFb facilitates BRD4-enhanced Pol II elongation. BRD4 binds to Kac sites on histones and recruits BRD4 interactors and the P-TEFb complex, leading to enhanced transcriptional elongation by Ser2-phosphorylated Pol II. (D) BRD4 function in DNA damage response in both NHEJ and HR pathways.

Figure 2.

Resistance mechanisms.

Figure 3.

Reported novel selective inhibitors 1−20. (A) Chemical structures of BRD4 BD1-selective inhibitors. The docking pose of compounds 2 and 6 with BRD4−BD1 in ribbon representation is shown on the right. Key residues, including Pro82, Gln85, Lys91, Tyr97, and Asn140, are shown in green sticks, and the amide ketone of compound 2 interacts with the critical conserved residue Asn140 to form a hydrogen bond. Similarly, in the docking pose of compound 6, key residues Asn140, Tyr97, Gln85, and Pro82 are green. The carbonyl O atom of compound 6 interacts with the conserved residue Asn140, forming a direct H bond, and with Tyr97, forming an indirect hydrogen bond mediated by a water molecule. (B) Reported BRD4 BD2-selective inhibitors. (C) Chemical structures of BRD4-selective inhibitors.

Figure 4.

Chemical structures of dual-target inhibitors 21−31.

Figure 5.

Reported PROTAC degraders and PPI inhibitors. (A) PROTAC degraders based on CRL4^CRBN (32−38) and CRL2^VHL E3 ligase (39−45). (B) Chemical structures of 46−48.