PROTACs are bivalent chemical protein degraders. In particular, PROTACs degrade a specific endogenous protein of interest (POI) by harnessing the E3 ubiquitin ligase pathway. Especially, PROTACs is a powerful small-molecule approach for inducing protein degradation. Moreover, PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Triazolodiazepine PROTACs exhibits positive cooperativities of ternary complex formation. MZP-54 acts as a selective PROTAC degrader of BRD3/4.

Bromodomain and extra-terminal (BET)-targeting PROTACs could provide advantageous therapeutic profiles over BET inhibitors. The BET family proteins have a role in the pathogenesis and progression of osteosarcoma. BET PROTACs represent a promising therapeutic agent for human osteosarcoma. Besides, BET PROTACs are bifunctional molecules with one side bound to BET proteins and the other side recognized by the Cullin-dependent E3 ligase. Furthermore, BET proteins BRD2, BRD3, and BRD4 play important roles in epigenetics, and cancer. The BET family of proteins, including the ubiquitously expressed BRD2, BRD3, and BRD4 and the testis-specific BRDT, recruit transcriptional regulatory complexes to acetylated chromatin. As a result, BET proteins control specific networks of genes involved in cellular proliferation and cell cycle progression.

MZP-54 act as a selective degrader of BRD3/4 within the appropriate window of concentration (30–100 nM). In addition, MZP-54 shows antiproliferative Activity in MV4;11 and HL60 cells with pEC50s of 7.31±0.03 and 6.57±0.02, respectively.

In summary, MZP-54 is a selective small-molecule degrader of BET. The acute, profound, and reversible effect make MZP-54 an advantageous approach to study the function of BET proteins in physiological and disease cellular state.

Kwok-Ho Chan, et al. Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds. J Med Chem. 2018 Jan 25;61(2):504-513.