MZP-55 is a selective PROTAC degrader of BRD3/4, shows no obvious effect on BRD2. MZP-55 exhibits excellent activity in cancer research.

PROTAC (proteolysis targeting chimera) is a chimera, functions to degrade certain proteins. It is composed of two headed molecules as well as a linker. One is able to bind to E3 ubiquitin ligase, and the other binds to the target protein. A PROTAC works by recruitment of the E3 ligase to the unwanted protein, and leads to degradation of the protein by proteasome. Many PROTAC are used in the cancer research. We need to find out more inhibitors of the target proteins.

Recently, Kwok-Ho Chan, et al explored a novel PROTAC named MZP-55, effectively inhibits BET proteins. BET protein (Bromodomain and extraterminal domain) include BRD2, BRD3, BRD4 and BRDT. MZP-55 is a selective degrader of BRD3/4.

MZP-55 consists of a BET inhibitor and a ligand of E3 ligase VHL via a PEG linker. It causes significant inhibition of BET proteins in a concentration dependent manner. It markedly degrades BRD3/4, shows no obvious effect on BRD2. But interestingly, The PROTAC increases BET protein levels at concentrations in the range from 1 μM to 10 μM.

With excellent activity against BET protein, MZP-55 also exhibits potent anti-tumor effects.

Researchers carried out the in vitro assay in acute myeloid leukemia (AML). MZP-55 causes significant depletion of Brd4 and cMyc in MV4;11 and HL60 cells. The pEC50 values are 7.08 and 6.37, respectively.

In the future, we need to do further research about the PROTAC.

1. Chan KH, et al. J Med Chem. 2018 Jan 25;61(2):504-513.