Work at the Milner Therapeutics Institute by Director Tony Kouzarides and Kostas Tzelepis in collaboration with Storm Therapeutics has made a promising step towards developing a new drug for treating acute myeloid leukaemia. In a paper published today in Nature, Kouzarides and colleagues report a new approach to cancer treatment that targets an RNA modifying enzyme METTL3 – known to have a key role in translating DNA into proteins. This is the first time an RNA-modification pathway has been targeted as a strategy to fight cancer, and the STORM METTL3 inhibitor will enter clinical trials in 2022.
“This is a brand-new field of research for cancer and the first drug of its type to be developed” said Kouzarides. “Its success at killing leukaemia cells and prolonging the lifespans of our mice is very promising for clinical trials” said Tzelepis. “We also believe that this new approach – of targeting these enzymes – could be a new weapon in our arsenal against many types of cancer”.
Read the press release from the University of Cambridge.
Small molecule inhibition of METTL3 as a therapeutic strategy for acute myeloid leukaemia
Yankoka, E, et al. Nature; 26 Apr 2021; DOI: 10.1038/s41586-021-03536-w.
Abstract from the paper
The N6-methyladenosine (m6A) is an abundant internal RNA modification catalysed predominantly by the METTL3–METTL14 methyltransferase complex. The m6A writer METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but its true therapeutic importance is still unknown.
Here we present the identification and characterisation of a METTL3 inhibitor (STM2457) along with a co-crystal with the METTL3 enzyme. We demonstrate that this highly potent and selective first-in-class catalytic inhibitor of METTL3 is effective as a new therapeutic strategy against AML. Inhibition of METTL3 in AML cells leads to a reduction in cell growth, and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect.
We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in a variety of primary AML models, specifically targeting key stem cell subpopulations of AML.
Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA modifying enzymes represents a promising new avenue for anti-cancer therapy.