Recently, a research team led by Prof. LIU Qingsong from Hefei Institutes of Physical Science (HFIPS), Chinese Academy of Sciences, discovered a novel covalent EZH2 degrader IHMT-EZH2-426.
Their findings, published in European Journal of Medicinal Chemistry, hold promise for combating triple-negative breast cancer (TNBC) and other types of cancer.
EZH2 is a protein that is often overexpressed in various cancers, including TNBC, and its high levels are associated with poor prognosis. However, solely inhibiting the enzymatic activity of EZH2 without decreasing its expression has proven insufficient in curbing the growth of breast cancer cells. The EZH2 degrader, inhibiting the enzymatic activities of EZH2 as well as degrading EZH2, is a novel strategy for the treatment of TNBC.
In this study, the researchers discovered a novel EZH2 down regulator IHMT-EZH2-426 using the covalent drug design and medicinal chemistry approaches based on EPZ6438. This degrader forms a covalent bond with the residue Cys663 of EZH2.
In laboratory experiments, it displayed strong activities against both EZH2 WT and EZH2 mutants, potentially reducing the levels of EZH2 and H3K27me3 in B cell lymphoma and TNBC cell lines. Moreover, IHMT-EZH2-426 successfully inhibited the proliferation of these cancer cells.
To validate the mechanism of action, the researchers conducted washout and competitive experiments, along with mass spectrometry analysis, which confirmed the formation of the covalent bond between IHMT-EZH2-426 and EZH2. In vivo, IHMT-EZH2-426 exhibited better efficacy than EPZ-6438 in MDA-MB-231 cell-mediated xenograft mouse models. Meanwhile, it displayed effective tumor suppression activity in Pfeiffer cell-mediated xenograft mouse models.
These results demonstrated that the covalent EZH2 inhibitor can offer a new opportunity for the development of promising new-generation drug candidates.
Anti-tumor efficacy evaluation of IHMT-EZH2-426(Compd. 38) in xenograft mouse models (Image by ZHOU Bin)
