Acute leukemias and other blood cancer subtypes rely on a variety of mechanisms to keep aggressive cancer cells growing. EZH2, a chromatin-modulating enzyme, and cMyc, a well-known cancer-causing factor, are notable examples of these mechanisms. Researchers at UNC have now demonstrated that these two factors are capable of forming direct connections and influencing the gene expression programs specific to cancer cells.
With the help of Mount Sinai’s Icahn School of Medicine, they came up with MS177, a small molecule based on the proteolysis-targeting chimera (PROTAC) technology that could target both EZH2 and cMyc. MS177 inhibits cancer growth by targeting both EZH2 and cMyc.
Nature Cell Biology has published their findings.
Associate professor of Biochemistry and Biophysics and Pharmacology at the UNC School of Medicine Greg Wang, PhD, and co-lead author of this study, said that EZH2 “EZH2 plays a very important role during cancer progression and is a known target suitable for drug development,” Small-molecule PROTAC’s ability to target EZH2 and cMyc in cancer cells at the same time astounds us.
They discovered that EZH2 binds to chromatin in acute leukemia cells in two distinct ways, resulting in two distinct gene-regulatory programs. As part of a canonical protein complex, known as PRC2, EZH2 suppresses gene expression in a set of genomic regions. However, EZH2 interacts with cMyc to activate gene expression in genomic regions that are distinct from the previously mentioned ones. EZH2 small-molecule inhibitors can’t completely block EZH2 because of this. Jun Wang, PhD, postdoctoral researcher at UNC Lineberger and co-first author of the work, said: “PROTAC addresses this gap.”
According to the findings, MS177 kills cancer cells while also causing significant side effects in healthy cells. Patients with acute leukemia are more likely to benefit from MS177 than current enzymatic inhibitors.” EZH2 and cMyc have never been the subject of a dual-targeting agent before, to the best of our knowledge. “cMyc is difficult to ‘drug,'” said Greg Wang. According to the above tumorigenic pathways, MS177 is a promising candidate for treating other cancers.
