In a recent study published in Angewandte Chemie, researchers have found that a metal compound can inhibit an enzyme strongly linked to triple-negative breast cancer (TNBC), an aggressive form of breast cancer that is highly challenging to treat.
Lysine-specific demethylase 5A is an enzyme encoded by the KDM5A gene, which is overexpressed in breast cancer as well as in brain, lung, and gastric cancers. KDM5A promotes carcinogenesis and drug resistance. A small number of KDM5A inhibitors have been found, but most are unable to effectively detect KDM5A and thus cannot restrain it successfully.
The researchers, led by Edmond Dik-Lung Ma, PhD, associate professor of chemistry at Hong Kong Baptist University, and by Chung-Hang Lung, PhD, professor at the Institute of Chinese Medical Sciences of the University of Macau, used rhodium (Rh) to design and synthesize metal complexes bearing ligands reported to have demethylase and p27 modulating activities. They found one compound, Rh(III) complex 1, that works as a "direct, selective, and potent" KDM5A inhibitor, according to the published article. As Dr. Ma explained, Rh(III) complex 1 nullifies KDM5A demethylase activity "by disrupting the interaction between KDM5A and trimethylated histone H3, a protein that regulates the folding of DNA. This leads to the accumulation of methylated marks on histone H3, which in turn increases the expression of p27, a protein that suppresses tumor growth."
Dr. Ma stated that when Rh(III) complex 1 was tested in TNBC cell lines, it was able to suppress cells' growth process. It also showed powerful anti-tumor activity in mice. Furthermore, it was less toxic in mouse models than two commonly used chemotherapy agents, cisplatin and doxorubicin.
In their published article, the authors state that to their knowledge, Rh(III) complex 1 is the first metal-based KDM5A inhibitor to be reported. They hope that it can be used "as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC."
Dr. Ma further emphasized the importance of the researchers' findings: "The traditional TNBC treatments are limited by drug resistance and serious side effects, including organ damage. Therefore, there is an urgent need to develop new targeted approaches for the treatment of TNBC. We therefore believe that our metal compound shows great promise for the development of targeted drugs for TNBC therapy."
For More Information
Yang GJ, Wang W, Mok SWF, et al (2018). Selective inhibition of lysine-specific demethylase 5A (KDM5A) using a rhodium(III) complex for triple-negative breast cancer therapy. Angew Chem Int Ed Engl. [Epub ahead of print] DOI:10.1002/anie.201807305